Alpha, beta-unsaturated sulfoxides for treating proliferative disorders

ABSTRACT

αβ-Unsaturated sulfoxides of Formula I:  
                 
are useful as antiproliferative agents including, for example, anticancer agents, and as radioprotective and chemoprotective agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of copending U.S. ProvisionalApplication Ser. No. 60/520,523, filed Nov. 14, 2003, the entiredisclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to compositions and methods for the treatment ofproliferative disorders, including but not limited to cancer. Theinvention further relates to compositions that afford protection fromthe cytotoxic effects of ionizing radiation and of cytotoxicchemotherapeutic agents.

BACKGROUND OF THE INVENTION

Ionizing Radiation Health Risks

Ionizing radiation has an adverse effect on cells and tissues, primarilythrough cytotoxic effects. In humans, exposure to ionizing radiationoccurs primarily through therapeutic techniques (such as anticancerradiotherapy) or through occupational and environmental exposure.

Therapeutic Administration of Radiation

A major source of exposure to ionizing radiation is the administrationof therapeutic radiation in the treatment of cancer or otherproliferative disorders. Depending on the course of treatment prescribedby the treating physician, multiple doses may be received by anindividual over the course of several weeks to several months.

Therapeutic radiation is generally applied to a defined area of theindividual's body which contains abnormal proliferative tissue, in orderto maximize the dose absorbed by the abnormal tissue and minimize thedose absorbed by the nearby normal tissue. However, it is difficult (ifnot impossible) to selectively administer therapeutic ionizing radiationto the abnormal tissue. Thus, normal tissue proximate to the abnormaltissue is also exposed to potentially damaging doses of ionizingradiation throughout the course of treatment.

There are also some treatments that require exposure of the individual'sentire body to the radiation, in a procedure called “total bodyirradiation”, or “TBI.” The efficacy of radiotherapeutic techniques indestroying abnormal proliferative cells is therefore balanced byassociated cytotoxic effects on nearby normal cells. Because of this,radiotherapy techniques have an inherently narrow therapeutic indexwhich results in the inadequate treatment of most tumors. Even the bestradiotherapeutic techniques may result in incomplete tumor reduction,tumor recurrence, increasing tumor burden, and induction of radiationresistant tumors.

Numerous methods have been designed to reduce normal tissue damage whilestill delivering effective therapeutic doses of ionizing radiation.These techniques include brachytherapy, fractionated andhyperfractionated dosing, complicated dose scheduling and deliverysystems, and high voltage therapy with a linear accelerator. However,such techniques only attempt to strike a balance between the therapeuticand undesirable effects of the radiation, and full efficacy has not beenachieved.

For example, one treatment for individuals with metastatic tumorsinvolves harvesting their hematopoietic stem cells and then treating theindividual with high doses of ionizing radiation. This treatment isdesigned to destroy the individual's tumor cells, but has the sideeffect of also destroying their normal hematopoietic cells. Thus, aportion of the individual's bone marrow (containing the hematopoieticstem cells), is removed prior to radiation therapy. Once the individualhas been treated, the autologous hematopoietic stem cells are returnedto their body.

However, if tumor cells have metastasized away from the tumor's primarysite, there is a high probability that some tumor cells will contaminatethe harvested hematopoietic cell population. The harvested hematopoieticcell population may also contain neoplastic cells if the individualsuffers from cancers of the bone marrow such as the variousFrench-American-British (FAB) subtypes of acute myelogenous leukemias(AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia(ALL). Thus, the metastasized tumor cells or resident neoplastic cellsmust be removed or killed prior to reintroducing the stem cells to theindividual. If any living tumorigenic or neoplastic cells arere-introduced into the individual, they can lead to a relapse.

Prior art methods of removing tumorigenic or neoplastic cells fromharvested bone marrow are based on a whole-population tumor cellseparation or killing strategy, which typically does not kill or removeall of the contaminating malignant cells. Such methods includeleukopheresis of mobilized peripheral blood cells, immunoaffinity-basedselection or killing of tumor cells, or the use of cytotoxic orphotosensitizing agents to selectively kill tumor cells. In the bestcase, the malignant cell burden may still be at 1 to 10 tumor cells forevery 100,000 cells present in the initial harvest (Lazarus et al. J. ofHematotherapy, 2(4):457-66, 1993).

Thus, there is needed a purging method designed to selectively destroythe malignant cells present in the bone marrow, while preserving thenormal hematopoietic stem cells needed for hematopoietic reconstitutionin the transplantation subject.

Occupational/Environmental Radiation Exposure

Exposure to ionizing radiation can also occur in the occupationalsetting. Occupational doses of ionizing radiation may be received bypersons whose job involves exposure (or potential exposure) toradiation, for example in the nuclear power and nuclear weaponsindustries. Military personnel stationed on vessels powered by nuclearreactors, or soldiers required to operate in areas contaminated byradioactive fallout, risk similar exposure to ionizing radiation.Occupational exposure may also occur in rescue and emergency personnelcalled in to deal with catastrophic events involving a nuclear reactoror radioactive material. Other sources of occupational exposure may befrom machine parts, plastics, and solvents left over from themanufacture of radioactive medical products, smoke alarms, emergencysigns, and other consumer goods. Occupational exposure may also occur inpersons who serve on nuclear powered vessels, particularly those whotend the nuclear reactors, in military personnel operating in areascontaminated by nuclear weapons fallout, and in emergency personnel whodeal with nuclear accidents. Environmental exposure to ionizingradiation may also result from nuclear weapons detonations (eitherexperimental or during wartime), discharges of actinides from nuclearwaste storage and processing and reprocessing of nuclear fuel, and fromnaturally occurring radioactive materials such as radon gas or uranium.There is also increasing concern that the use of ordnance containingdepleted uranium results in low-level radioactive contamination ofcombat areas.

Radiation exposure from any source can be classified as acute (a singlelarge exposure) or chronic (a series of small low-level, or continuouslow-level exposures spread over time). Radiation sickness generallyresults from an acute exposure of a sufficient dose, and presents with acharacteristic set of symptoms that appear in an orderly fashion,including hair loss, weakness, vomiting, diarrhea, skin burns andbleeding from the gastrointestinal tract and mucous membranes. Geneticdefects, sterility and cancers (particularly bone marrow cancer) oftendevelop over time. Chronic exposure is usually associated with delayedmedical problems such as cancer and premature aging. An acute a totalbody exposure of 125,000 millirem may cause radiation sickness.Localized doses such as are used in radiotherapy may not cause radiationsickness, but may result in the damage or death of exposed normal cells.

For example, an acute total body radiation dose of 100,000-125,000millirem (equivalent to 1 Gy) received in less than one week wouldresult in observable physiologic effects such as skin burns or rashes,mucosal and GI bleeding, nausea, diarrhea and/or excessive fatigue.Longer term cytotoxic and genetic effects such as hematopoietic andimmunocompetent cell destruction, hair loss (alopecia),gastrointestinal, and oral mucosal sloughing, venoocclusive disease ofthe liver and chronic vascular hyperplasia of cerebral vessels,cataracts, pneumonites, skin changes, and an increased incidence ofcancer may also manifest over time. Acute doses of less than 10,000millirem (equivalent to 0.1 Gy) typically will not result in immediatelyobservable biologic or physiologic effects, although long term cytotoxicor genetic effects may occur.

A sufficiently large acute dose of ionizing radiation, for example500,000 to over I million millirem (equivalent to 5-10 Gy), may kill anindividual immediately. Doses in the hundreds of thousands of milliremsmay kill within 7 to 21 days from a condition called “acute radiationpoisoning.” Reportedly, some of the Chernobyl firefighters died of acuteradiation poisoning, having received acute doses in the range of200,000-600,000 millirem (equivalent to 2-6 Gy). Acute doses belowapproximately 200,000 millirem do not result in death, but the exposedindividual will likely suffer long-term cytotoxic or genetic effects asdiscussed above.

Acute occupational exposures usually occur in nuclear power plantworkers exposed to accidental releases of radiation, or in fire andrescue personnel who respond to catastrophic events involving nuclearreactors or other sources of radioactive material. Suggested limits foracute occupational exposures in emergency situations were developed bythe Brookhaven National Laboratories, and are given in Table 1. TABLE 1Whole Body Conditions for Dose Limit Activity Required Conditions forExposure 10,000 millirem* Protect property Voluntary, when lower dosenot practical 25,000 millirem Lifesaving Voluntary, when lower doseOperation; not practical Protect General Public >25,000 milliremLifesaving Voluntary, when lower dose operation; not practical, and therisk Protect large has been clearly explained population*100,000 millirem equals one sievert (Sv). For penetrating radiationsuch as gamma radiation, one Sv equals approximately one Gray (Gy).Thus, the dosage in Gy can be estimated as 1 Gy for every 100,000millirem.

A chronic dose is a low level (i.e., 100-5000 millirem) incremental orcontinuous radiation dose received over time. Examples of chronic dosesinclude a whole body dose of ˜5000 millirem per year, which is the dosetypically received by an adult working at a nuclear power plant. Bycontrast, the Atomic Energy Commission recommends that members of thegeneral public should not receive more than 100 millirem per year.Chronic doses may cause long-term cytotoxic and genetic effects, forexample manifesting as an increased risk of a radiation-induced cancerdeveloping later in life. Recommended limits for chronic exposure toionizing radiation are given in Table 2. TABLE 2 Annual OccupationalOrgan or Subject Dose in millirem Whole Body 5000 Lens of the Eye 15,000Hands and wrists 50,000 Any individual organ 50,000 Pregnant worker500/9 months Minor (16-18) receiving training 100

By way of comparison, Table 3 sets forth the radiation doses from commonsources. TABLE 3 Sources Dose In Millirem Television <1/yr Gamma Rays,Jet Cross Country 1 Mountain Vacation - 2 week 3 Atomic Test Fallout 5U.S. Water, Food & Air (Average) 30/yr Wood 50/yr Concrete 50/yr Brick75/yr Chest X-Ray 100 Cosmic Radiation (Sea Level) 40/yr (add 1millirem/100 ft elev.) Natural Background San Francisco 120/yr NaturalBackground Denver 50/yr Atomic Energy Commission Limit 5000/yr ForWorkers Complete Dental X-Ray 5000 Natural Background at Pocos de7000/yr Caldras, Brazil Whole Body Diagnostic X-Ray 100,000 CancerTherapy 500,000 (localized) Radiation Sickness-Nagasaki 125,000 (singledoses) LD₅₀ Nagasaki & Hiroshima 400,000-500,000 (single dose)

Chronic doses of greater than 5000 millirem per year (0.05 Gy per year)may result in long-term cytotoxic or genetic effects similar to thosedescribed for persons receiving acute doses. Some adverse cytotoxic orgenetic effects may also occur at chronic doses of significantly lessthan 5000 millirem per year. For radiation protection purposes, it isassumed that any dose above zero can increase the risk ofradiation-induced cancer (i.e., that there is no threshold).Epidemiologic studies have found that the estimated lifetime risk ofdying from cancer is greater by about 0.04% per rem of radiation dose tothe whole body.

While anti-radiation suits or other protective gear may be effective atreducing radiation exposure, such gear is expensive, unwieldy, andgenerally not available to public. Moreover, radioprotective gear willnot protect normal tissue adjacent a tumor from stray radiation exposureduring radiotherapy. What is needed, therefore, is a practical way toprotect individuals who are scheduled to incur, or are at risk forincurring, exposure to ionizing radiation. In the context of therapeuticirradiation, it is desirable to enhance protection of normal cells whilecausing tumor cells to remain vulnerable to the detrimental effects ofthe radiation. Furthermore, it is desirable to provide systemicprotection from anticipated or inadvertent total body irradiation, suchas may occur with occupational or environmental exposures, or withcertain therapeutic techniques.

Pharmaceutical radioprotectants offer a cost-efficient, effective andeasily available alternative to radioprotective gear. However, previousattempts at radioprotection of normal cells with pharmaceuticalcompositions have not been entirely successful. For example, cytokinesdirected at mobilizing the peripheral blood progenitor cells confer amyeloprotective effect when given prior to radiation (Neta et al.,Semin. Radial. Oncol. 6:306-320, 1996), but do not confer systemicprotection. Other chemical radioprotectors administered alone or incombination with biologic response modifiers have shown minor protectiveeffects in mice, but application of these compounds to large mammals wasless successful, and it was questioned whether chemical radioprotectionwas of any value (Maisin, J. R., Bacq and Alexander Award Lecture.“Chemical radioprotection: past, present, and future prospects”, Int J.Radial Biol. 73:443-50, 1998). Pharmaceutical radiation sensitizers,which are known to preferentially enhance the effects of radiation incancerous tissues, are clearly unsuited for the general systemicprotection of normal tissues from exposure to ionizing radiation.

What is needed are therapeutic agents to protect individuals who haveincurred, or are at risk for incurring exposure to ionizing radiation.In the context of therapeutic irradiation, it is desirable to enhanceprotection of normal cells while causing tumor cells to remainvulnerable to the detrimental effects of the radiation. Furthermore, itis desirable to provide systemic protection from anticipated orinadvertent total body irradiation, such as may occur with occupationalor environmental exposures, or with certain therapeutic techniques.

Protection from Toxic Side Effects of Experimental Chemotherapy

Experimental chemotherapy has been the mainstay of treatment offered topatients diagnosed with surgically unresectable advanced cancers, orcancers refractory to standard chemotherapy and radiation therapy. Ofthe more effective classes of drugs, curative properties are stilllimited. This is because of their relatively narrow therapeutic index,restricted dosage, delayed treatments and a relatively large proportionof only partial tumor reductions. This state is usually followed byrecurrence, increased tumor burden, and drug resistant tumors.

Several cytoprotective agents have been proposed to enhance thetherapeutic index of anticancer drugs. For methotrexate toxicity, suchagents include asparaginase, leucovorum factor, thymidine, andcarbipeptidase. Because of the extensive use of anthracyclines, specificand non-specific cytoprotective agents have been proposed which havevarying degrees of efficacy; included are corticosteroids, desrazoxaneand staurosporin. The latter is of interest in that it includes a G1/Srestriction blockade in normal cells. (Chen et al., Proc AACR 39:4436A,1998).

Cisplatin is widely used and has a small therapeutic index which hasspurred investigation and search of cytoprotectants. Among thecytoprotectants for cisplatin with clinical potential are mesna,glutathione, sodium thiosulfate, and amifostine (Griggs, Leuk. Res. 22Suppl 1:S27-33, 1998; List et al., Semin. Oncol. 23(4 Suppl 8):58-63,1996; Taylor et. al., Eur. J. Cancer 33(10):1693-8, 1997). None of theseor other proposed cytoprotectants such as oxonic acid forfluoropyrimidine toxicity, or prosaptide for paclitaxel PC12 celltoxicity, appears to function by a mechanism which renders normalreplicating cells into a quiescent state.

What is needed are new effective cytoprotective agents which areeffective in protecting animals, inclusive of humans, from the cytotoxicside effects of chemotherapeutic agents.

α,β-Unsaturated Sulfone Compounds

Certain α,β-unsaturated sulfones, particularly styrylbenzyl sulfoneshave been shown to posses antiproliferative, radioprotective andchemoprotective activity. See, U.S. Pat. Nos. 6,599,932, 6,576,675,6,548,553, 6,541,475, 6,486,210, 6,414,034, 6,359,013, 6,201,154,6,656,973 and 6,762,207, the entire disclosures of which areincorporated herein.

Metabolic Sulfoxide Oxidation

Sulfoxide functional groups are metabolically oxidized to thecorresponding sulfones via the cytochrome P-450 family of oxidizingenzymes. Cytochrome P-450 enzymes are iron-based proteins that mediateredox reactions wherein a substrate, e.g., a drug molecule, is oxidizedand the iron is reduced.

The oxidative metabolism of sulfoxide moieties has been employed byadministering sulfoxide compounds that are metabolically converted toactive metabolite sulfone compounds. One example of this strategy is theadministration of sulindac sulfoxide, a commonly prescribedantiinflammatory drug has been shown to additionally have cancerchemopreventative activity. See, Thompson et al., Cancer Research, Jan.15, 1997; 57(2), pg. 267-271.

The sulindac sulfoxide possesses no antiinflammatory activity but israther a prodrug that is converted metabolically to the active sulfide.Once administered, the sulindac sulfoxide is readily reduced to theantiinflammatory sulfide form in the liver and in the colon viabacterial microflora. However, the sulindac sulfoxide is alsometabolically oxidized in the liver to the sulfone that is subsequentlyexcreted in the bile and intestine. The sulfone metabolite has noantiinflammatory activity, however the sulfone still retains the abilityto inhibit tumor cell growth and induce apoptosis. See S. M. Fischer,Frontiers in Bioscience, 2, pg. 482-500, (1997).

DEFINITIONS

General

The term “individual” or “subject”, includes human beings and non-humananimals. With respect to the disclosed radioprotective andcytoprotective methods, these terms refer, unless the context indicatesotherwise, to an organism that is scheduled to incur, or is at risk forincurring, or has incurred, exposure to ionizing radiation or exposureto one or more cytotoxic chemotherapeutic agents.

The expression “effective amount” when used to describe therapy to apatient suffering from a proliferative disorder, refers to the amount ofa compound of Formula I that inhibits the growth of tumor cells oralternatively induces apoptosis of cancer cells, preferably tumor cells,resulting in a therapeutically useful and selective cytotoxic effect onproliferative cells when administered to a patient suffering from acancer or other disorder which manifests abnormal cellularproliferation. The term “effective amount” is inclusive of amounts of acompound of Formula I that is metabolized to an active metabolite in anamount that inhibits the growth of tumor cells or induces apoptosis ofcancer cells.

The term “antibody” is intended to encompass not only intactantigen-binding immunoglobulin molecules, but also to includeantigen-binding fragments thereof such as Fab, Fab′ and F(ab′)₂fragments, or any other fragment retaining the antigen-binding abilityof an intact antibody.

The expression “humanized antibody” refers to an antibody that has itscomplementary determining regions (CDR's) derived from a non-humanspecies immunoglobulin, and the remainder of the antibody moleculederived from a human immunoglobulin.

The expression “chimeric antibody” means an antibody comprising avariable region and a constant region derived from different species.

The expression “humanized chimeric antibody” is meant a chimericantibody in which at least the constant region is human-derived.

The expression “monospecific polyclonal antibody” means an antibodypreparation comprising multiple antibody species having specificity fora single antigen.

The term “proliferative disorder” means a disorder wherein cells aremade by the body at an atypically accelerated rate.

Radioprotection

As used herein, “ionizing radiation” is radiation of sufficient energythat, when absorbed by cells and tissues, induces formation of reactiveoxygen species and DNA damage. This type of radiation includes X-rays,gamma rays, and particle bombardment (e.g., neutron beam, electron beam,protons, mesons and others), and is used for medical testing andtreatment, scientific purposes, industrial testing, manufacturing andsterilization, weapons and weapons development, and many other uses.Radiation is typically measured in units of absorbed dose, such as therad or gray (Gy), wherein 1 rad=0.01 Gy, or in units of doseequivalence, such as the rem or sievert (Sv), wherein 1 rem=0.01 Sv.

The Sv is the Gy dosage multiplied by a factor that includes tissuedamage done. For example, penetrating ionizing radiation (e.g., gammaand beta radiation) have a factor of about 1, so 1 Sv=˜1 Gy. Alpha rayshave a factor of 20, so 1 Gy of alpha radiation=20 Sv.

By “effective amount of ionizing radiation” is meant an amount ofionizing radiation effective in killing, or in reducing theproliferation, of abnormally proliferating cells in an individual. Asused with respect to bone marrow purging, “effective amount of ionizingradiation” means an amount of ionizing radiation effective in killing,or in reducing the proliferation, of malignant cells in a bone marrowsample removed from an individual.

By “acute exposure to ionizing radiation” or “acute dose of ionizingradiation” is meant a dose of ionizing radiation absorbed by anindividual in less than 24 hours. The acute dose may be localized, as inradiotherapy techniques, or may be absorbed by the individual's entirebody. Acute doses are typically above 10,000 millirem (0.1 Gy), but maybe lower.

By “chronic exposure to ionizing radiation” or “chronic dose of ionizingradiation” is meant a dose of ionizing radiation absorbed by anindividual over a period greater than 24 hours. The dose may beintermittent or continuous, and may be localized or absorbed by theindividual's entire body. Chronic doses are typically less than 10,000millirem (0.1 Gy), but may be higher.

By “at risk of incurring exposure to ionizing radiation” is meant thatan individual may intentionally, e.g., by scheduled radiotherapysessions, or inadvertently be exposed to ionizing radiation in thefuture. Inadvertent exposure includes accidental or unplannedenvironmental or occupational exposure.

By “effective amount of a radioprotective compound” is meant an amountof compound of Formula I effective to reduce or eliminate the toxicityassociated with radiation in normal cells of the individual, and also toimpart a direct cytotoxic effect to abnormally proliferating cells inthe individual. As used with respect to bone marrow purging, “effectiveamount” of the radioprotective compound of Formula I means an amount ofcompound effective to reduce or eliminate the toxicity associated withradiation in bone marrow removed from an individual, and also to imparta direct cytotoxic effect to malignant cells in the bone marrow removedfrom the individual.

Cytoprotection

By “effective amount” of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor is meant an amount of said inhibitor effectivein killing or reducing the proliferation of cancer cells in a hostanimal.

By “effective amount” of the cytoprotective compound of Formula I ismeant an amount of compound effective to reduce the toxicity of themitotic phase cell cycle inhibitor or topoisomerase inhibitor on normalcells of the animal.

The expression “cell cycle” refers to the usual description of celldevelopment in terms of a cycle consisting of a series ofphases—interphase and M (mitotic) phase—and the subdivision ofinterphase into the times when DNA synthesis is proceeding, known as theS-phase (for synthesis phase), and the gaps that separate the S-phasefrom mitosis. G1 is the gap after mitosis but before DNA synthesisstarts, and G2 is the gap after DNA synthesis is complete before mitosisand cell division. Interphase is thus composed of successive G1, S andG2 phases, and normally comprises 90% or more of the total cell cycletime. The M phase consists of nuclear division (mitosis) and cytoplasmicdivision (cytokinesis). During the early part of the M phase, thereplicated chromosomes condense from their extended interphasecondition. The nuclear envelope breaks down, and each chromosomeundergoes movements that result in the separation of pairs of sisterchromatids as the nuclear contents are divided. Two new nuclearenvelopes then form, and the cytoplasm divides to generate two daughtercells, each with a single nucleus. This process of cytokinesisterminates the M phase and marks the beginning of the interphase of thenext cell cycle. The daughter cells resulting from completion of the Mphase begin the interphase of a new cycle.

By “mitotic phase cell cycle inhibitor” is meant a chemical agent whosemechanism of action includes inhibition of a cell's passage through anyportion of the mitotic (M) phase of the cell cycle.

By “topoisomerase inhibitor” is meant a chemical agent whose mechanismof action includes interfering with the function of a topoisomerase.

By “topoisomerase” is meant an enzyme that catalyzes the conversion ofDNA from one topological form to another by introducing transient breaksin one or both strands of a DNA duplex.

“Topological isomers” are molecules that differ only in their state ofsupercoiling. Type I topoisomerase cuts one strand of DNA and relaxesnegatively supercoiled DNA, but does not act on positively supercoiledDNA. Type II topoisomerase cuts both strands of DNA and increases thedegree of negative supercoiling in DNA.

Chemical

The term “alkenyl” employed alone or in combination with other terms,means, unless otherwise stated, a stable straight chain, branched chainor cyclic hydrocarbon group having the stated number of carbon atoms andcontaining at least one carbon-carbon double bond. Examples includevinyl, propenyl(allyl), crotyl, isopentenyl, butadienyl,1,3-pentadienyl, 1,4-pentadienyl, cyclopentenyl, cyclopentadienyl andthe higher homologs and isomers. A divalent radical derived from analkene is exemplified by —CH═CH—CH₂—.

The term “alkyl”, by itself or as part of another substituent, e.g.,alkoxy, haloalkyl or aminoalkyl, means, unless otherwise stated, asaturated hydrocarbon radical having the number of carbon atomsdesignated (i.e. C₁-C₆ means one to six carbons) and includes straight,branched chain, cyclic and polycyclic groups. Examples include: methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,neopentyl, hexyl, cyclohexyl, norbornyl and cyclopropylmethyl. Mostpreferred is (C₁-C₃)alkyl, particularly ethyl, methyl and isopropyl.

Substituted alkyl or alkenyl means alkyl or alkenyl, as defined above,substituted by one, two or three substituents selected from the groupconsisting of halogen, —OH, —O(C₁-C₄)alkyl, —NH₂, —N(CH₃)₂, —CO₂H,—CO₂(C₁-C₄)alkyl, —CF₃, —CONH₂, —SO₂NH₂, —C(═NH)NH₂, —CN and —NO₂,preferably containing one or two substituents selected from halogen,—OH, —NH₂, —N(CH₃)₂, trifluoromethyl and —O₂H, more preferably selectedfrom halogen and —OH. Examples of substituted alkyls include, but arenot limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and3-chloropropyl.

The term “alkylene”, by itself or as part of another substituent means,unless otherwise stated, a divalent straight, branched or cyclic chainhydrocarbon radical.

The term “alkoxy” employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group having the designatednumber of carbon atoms, as defined above, connected to the rest of themolecule via an oxygen atom, such as, for example, methoxy, ethoxy,1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.Preferred are (C₁-C₃)alkoxy, particularly ethoxy and methoxy.

The term “amine” or “amino” refers to radicals of the general formula—NRR′, wherein R and R′ are independently selected from hydrogen or ahydrocarbyl radical, or wherein R and R′ combined form a heterocycle.

Examples of amino groups include: —NH₂, methyl amino, diethyl amino,anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (4n+2) delocalizedn (pi) electrons).

The term “aryl” employed alone or in combination with other terms,means, unless otherwise stated, a carbocyclic aromatic system containingone or more rings (typically one, two or three rings) wherein such ringsmay be attached together in a pendent manner, such as a biphenyl, or maybe fused, such as naphthalene. Examples include phenyl; anthracyl; andnaphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.

The term “aryl-(C₁-C₃)alkyl” means a radical wherein a one to threecarbon alkylene chain is attached to an aryl group, e.g.,—CH₂CH₂-phenyl. Preferred is aryl(CH₂)— and aryl(CH(CH₃))—. The term“substituted aryl-(C₁-C₃)alkyl” means an aryl-C₁-C₃)alkyl radical inwhich the aryl group is substituted. Preferred is substitutedaryl(CH₂)—. Similarly, the term “heteroaryl(C₁-C₃)alkyl” means a radicalwherein a one to three carbon alkylene chain is attached to a heteroarylgroup, e.g., —CH₂CH₂-pyridyl. Preferred is heteroaryl(CH₂)—. The term“substituted heteroaryl-(C₁-C₃)alkyl” means a heteroaryl-(C₁-C₃)alkylradical in which the heteroaryl group is substituted. Preferred issubstituted heteroaryl(CH₂)—.

The term “arylene,” by itself or as part of another substituent means,unless otherwise stated, a divalent aryl radical. Preferred are divalentphenyl radicals, particularly 1,4-divalent phenyl radicals.

The term “cycloalkyl” refers to ring-containing alkyl radicals. Examplesinclude cyclohexyl, cyclopentyl, cyclopropyl methyl and norbornyl

The terms “halo” or “halogen” by themselves or as part of anothersubstituent, e.g., haloalkyl, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, orbromine, more preferably, fluorine or chlorine.

The term “haloalkyl” means, unless otherwise stated, an alkyl group asdefined herein containing at least one halogen substituent and nosubstituent that is other than halogen. Multiple halogen substituents,up to substitution of all substitutable hydrogens on the alkyl group maybe the same or different.

The term “heteroalkyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainradical consisting of the stated number of carbon atoms and one, twothree or four heteroatoms selected from the group consisting of O, N,and S, and wherein the sulfur heteroatoms may be optionally oxidized andthe nitrogen heteroatoms may be optionally quaternized or oxidized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

The term “heteroalkenyl” by itself or in combination with another termmeans, unless otherwise stated, a stable straight or branched chainmonounsaturated or di-unsaturated hydrocarbon radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

The term “heterocycle” or “heterocyclyl” or “heterocyclic” by itself oras part of another substituent means, unless otherwise stated, anunsubstituted or substituted, stable, mono- or multicyclic heterocyclicring system which consists of carbon atoms and at least one heteroatomselected from the group consisting of N, O, and S, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen atom may be optionally quaternized. The heterocyclic system maybe attached, unless otherwise stated, at any heteroatom or carbon atomwhich affords a stable structure.

The term “heteroaryl” or “heteroaromatic” refers to a heterocycle havingaromatic character. A monocyclic heteroaryl group is a 5-, 6, or7-membered ring, examples of which are pyrrolyl, furyl, thienyl,pyridyl, pyrimidinyl and pyrazinyl. A polycyclic heteroaryl may comprisemultiple aromatic rings or may include one or more rings which arepartially saturated. Examples of polycyclic heteroaryl groups containinga partially saturated ring include tetrahydroquinolyl and2,3-dihydrobenzofuryl. For compounds of Formula I, the attachment pointon ring A or ring B is understood to be on an atom which is part of anaromatic monocyclic ring or a ring component of a polycyclic aromaticwhich is itself an aromatic ring.

Examples of non-aromatic heterocycles include monocyclic groups such as:Aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include: Pyridyl, pyrazinyl, pyrimidinyl,particularly 2- and 4-pyrimidinyl, pyridazinyl, thienyl, furyl,pyrrolyl, particularly 2-pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, particularly 3- and 5-pyrazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include: Indolyl, particularly 3-,4-, 5-, 6- and 7-indolyl, indolinyl, quinolyl, tetrahydroquinolyl,isoquinolyl, particularly 1- and 5-isoquinolyl,1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl, particularly 2-and 5-quinoxalinyl, quinazolinyl, phthalazinyl, 1,8-naphthyridinyl,1,4-benzodioxanyl, coumarin, dihydrocoumarin, benzofuryl, particularly3-, 4-, 1,5-naphthyridinyl, 5-, 6- and 7-benzofuryl,2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl, particularly3-, 4-, 5-, 6-, and 7-benzothienyl, benzoxazolyl, benzthiazolyl,particularly 2-benzothiazolyl and 5-benzothiazolyl, purinyl,benzimidazolyl, particularly 2-benzimidazolyl, benztriazolyl,thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, andquinolizidinyl.

The term “heteroarylene,” by itself or as part of another substituentmeans, unless otherwise stated, a divalent heteroaryl radical. Preferredare five- or six-membered monocyclic heteroarylene. More preferred areheteroarylene moieties comprising divalent heteroaryl rings selectedfrom pyridine, piperazine, pyrimidine, pyrazine, furan, thiophene,pyrrole, thiazole, imidazole and oxazole.

For compounds of the present invention, when an aromatic orheteroaromatic ring is attached to a position and the ring comprises apolycyclic ring which is partially saturated, the attachment point onthe aromatic or heteroaromatic ring is on a ring atom of an aromaticring component of the polycyclic ring. For example on the partiallysaturated heteroaromatic ring, 1,2,3,4-tetrahydroisoquinoline,attachment points would be ring atoms at the 5-, 6-, 7- and 8-positions.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative, not limiting.

The term “hydrocarbyl” refers to any moiety comprising only hydrogen andcarbon atoms. Preferred heteroaryl groups are (C₁-C₁₂)hydrocarbyl, morepreferred are (C₁-C₇)hydrocarbyl, most preferred are benzyl and(C₁-C₆)alkyl.

The expression “carboxy terminally linked peptidyl residue” refers to apeptide radical as a substituent on a molecule of Formula I. The radicalis bonded through the carboxyl functionality of the peptidyl residue toform a carboxamide or carboxylic ester as shown in a representativeexample in Scheme 1 below.

The amino acid residues comprising the amino terminally linked peptidylresidue may comprise natural or unnatural amino acids or a combinationthereof. Unnatural amino acids are amino acids other than the twentyessential amino acids. One example of an unnatural amino acid is aD-amino acid, i.e., an amino acid having a stereochemistry opposite thestereochemistry of natural L-amino acids. Another example of anunnatural amino acid is an amino acid having a side chain that differsfrom the side chains occurring in the natural amino acids, for exampleα-ethyl glycine or α-phenyl glycine. A third example is an amino acidhaving a backbone variation. Examples of amino acid backbone variationsinclude β-alanine and β-turn mimetics such as Freidinger's lactam. Afourth example of an unnatural amino acid is an amino acid having twoα-substituents, e.g., α,α-dimethyl glycine.

The amino terminus of the carboxy terminally linked peptidyl residue maybe an unsubstituted amino group, or may be substituted. Substitutions onthe amino terminus include mono- and di-(C₁-C₆ alkyl), —C(═O)(C₁-C₆alkyl), —C(═O)O(C₁-C₇)hydrocarbyl) and commonly employed nitrogenprotecting groups such as t-butoxycarbonyl (BOC), carbobenxyloxy (CBZ),2,4-dimethoxybenyl and FMOC.

The expression “amino terminally linked peptidyl residue” refers to apeptide radical as a substituent on a compound of Formula I. The radicalis bonded through the terminal amino functionality of the peptidylresidue to form a carboxamide, sulfonamide, urea or thiourea as shown ina representative example in Scheme 2 below.

The carboxy terminus of the amino terminally linked peptidyl residue maybe a free carboxyl group or a salt thereof, or may be derivatized as anester or amide. Suitable esters include alkyl, aryl and arylalkylesters. Suitable amides include the primary amide and secondary andtertiary amides comprising one or two nitrogen substituentsindependently selected from (C₁-C₃)alkyl, preferably methyl or ethyl;aryl, preferably phenyl; and aryl(C₁-C₃)alkyl groups, preferably benzylor substituted benzyl.

As with the carboxy terminally linked peptidyl residues, the amino acidscomprising the amino terminally linked peptidyl residue may comprisenatural or unnatural amino acids or a combination thereof.

The term “(C_(x)-C_(y))perfluoroalkyl,” wherein x<y, means an alkylgroup with a minimum of x carbon atoms and a maximum of y carbon atoms,wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkyl, more preferred is —(C₁-C₃)perfluoroalkyl, mostpreferred is —CF₃.

The term “trifluoro(C_(x)-C_(y))alkyl” means an alkyl group with aminimum of x carbon atoms and a maximum of y carbon atoms, wherein thethree hydrogen atoms on a terminal carbon (—CH₃) are replaced byfluorine atoms. Examples include —CH₂CF₃, —(CH₂)₂—CF₃ and —CH(CH₃)—CF₃.

The term “difluoro(C_(x)-C_(y))alkyl” means an alkyl group with aminimum of x carbon atoms and a maximum of y carbon atoms, wherein onecarbon atom is geminally substituted with two fluorine atoms. Thefluorine-substituted carbon may be the any carbon in the chain having atleast two substitutable hydrogens, including the a terminal CH3 and theproximal carbon through which the difluoro(C_(x)-C_(y))alkyl is bondedto the rest of the molecule. Examples include —CH₂CF₂H, —(CH₂)₂—CF₂H and—CF₂—CH₃ and 3,3-difluorocyclohexyl.

The term “substituted” means that an atom or group of atoms has replacedhydrogen as the substituent attached to another group. For aryl andheteroaryl groups, the term “substituted” refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds, pharmaceuticalcompositions and therapeutic methods. The biologically active compoundsare in the form of α,β-unsaturated sulfoxides, and salts thereof.

It is an object of the invention to provide compounds, compositions andmethods for the treatment and/or prevention of cancer and otherproliferative disorders.

It is an object of the invention to provide compounds which areselective in killing tumor cells at therapeutically usefulconcentrations.

It is an object of the invention to provide compounds, compositions andmethods for inducing neoplastic cells to selectively undergo apoptosis.

It is a further object of this invention to provide compounds,compositions and methods which enable prophylactic treatment ofproliferative disorders.

It is a further object of this invention to provide compounds,compositions and methods for protecting normal cells and tissues fromthe cytotoxic and genetic effects of exposure to ionizing radiation, inindividuals who have incurred, will in the future incur, or are at riskfor incurring exposure to ionizing radiation.

The exposure to ionizing radiation may occur in controlled doses duringthe treatment of cancer and other proliferative disorders, or may occurin uncontrolled doses beyond the norm accepted for the population atlarge during high risk activities or environmental exposures.

It is an object of the invention to provide compositions and methods forprotecting individuals from the cytotoxic side effects ofchemotherapeutic agents, particularly mitotic phase cell cycleinhibitors and topoisomerase inhibitors, used in the treatment of cancerand other proliferative disorders.

It is an object of the invention provide a method for treating cancer orother proliferative disorder which reduces or eliminates cytotoxiceffects on normal cells.

It is an object of the invention to enhance the effects ofchemotherapeutic agents, particularly mitotic phase cell cycleinhibitors and topoisomerase inhibitors, used for the treatment ofcancer or other proliferative disorders.

It is an object of the present invention to provide a therapeuticprogram for treating cancer or other proliferative disorder whichincludes administration of a cytoprotective compound prior toadministration of a chemotherapeutic agent, which cytoprotectivecompound induces a reversible cycling quiescent state in non-tumoredtissues.

It is an object of the invention to provide a method for safelyincreasing the dosage of chemotherapeutic agents, particularly mitoticphase cell cycle inhibitors and topoisomerase inhibitors, used in thetreatment of cancer and other proliferative disorders.

According to one aspect, the invention is directed to novel compounds ofFormula I:

wherein:

A is substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

B is substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

n is 0 or 1; and

R′ is —H; —(C₁-C₈)hydrocarbyl, preferably —(C₁-C₆)alkyl, more preferably—(C₁-C₆)alkyl, most preferably —CH₃ or —C₂H₅; —CN; —CO₂(C₁-C₆)alkyl,preferably —CO₂(C₁-C₄)alkyl, most preferably —CO₂CH₃, —CO₂(ethyl) or—CO₂(t-butyl); or halo(C₁-C₆)alkyl, preferably trifluoro(C₁-C₆)alkyl ordifluoro(C₁-C₆)alkyl, more preferably trifluoro(C₁-C₃)alkyl ordifluoro(C₁-C₃)alkyl, most preferably —CF₃ or —CHF₂;

wherein:

the conformation of the substituents on the carbon-carbon double bond iseither E- or Z-;

the conformation of the substituents on the sulfoxide sulfur atom is R—,S— or any mixture of R— and S—;

* indicates that, when R′ is other than —H, the conformation of thesubstituents on the designated carbon atom is R—, S— or any mixture ofR— and S—; or a salt thereof;

provided that when A and B are both phenyl, at least one of A or B issubstituted.

According to some embodiments, A and B are independently selected fromthe group consisting of substituted and unsubstituted aryl.

According to other embodiments, A and B are independently selected fromthe group consisting of substituted and unsubstituted heteroaryl.

According to still other embodiments A is substituted or unsubstitutedaryl and B is substituted or unsubstituted heteroaryl.

According to still other embodiments B is substituted or unsubstitutedaryl and A is substituted or unsubstituted heteroaryl.

According to some embodiments, the conformation of the substituents onthe sulfoxide sulfur atom is a racemic mixture of R— and S—.

According to some embodiments, the conformation of the substituents onthe * designated carbon atom is a racemic mixture of R— and S—.

According to some embodiments, n is 1.

According to some embodiments, R¹ is —H

According to some sub-embodiments, the compounds of Formula I arecompounds of Formula Ie:

wherein the conformation of the substituents on the two carbons of thecarbon-carbon double bond is E-.

According to other sub-embodiments, the compounds of Formula I arecompounds of Formula Iz:

wherein the conformation of the substituents on two carbons of thecarbon-carbon double bond is Z-.

Substituents for substituted aryl and heteroaryl groups comprising A andB are preferably independently selected from the group consisting ofhalogen; —(C₁-C₈)hydrocarbyl, preferably —(C₁-C₆)alkyl, more preferably—(C₁-C₃)alkyl, most preferably —CH₃ and —C₂H₅; —C(═O)R²; —NR² ₂;—NHC(═O)R³; —NHSO₂R³; —NHR⁴; —NHCR²R⁴C(═O)R⁶; —NHSO₂R³; —C(═O)OR²;—C(═O)NHR²; —NO₂; —CN; —OR²; —P(═O)(OH)₂; dimethylamino(C₂-C₆ alkoxy);—NHC(═NR²)NHR²; —(C₁-C₆)haloalkyl, preferably trifluoro(C₁-C₆)alkyl anddifluoro(C₁-C₆)alkyl, more preferably trifluoro(C₁-C₃)alkyl anddifluoro(C₁-C₃)alkyl, most preferably —CF₃ and —CHF₂;—(C₁-C₆)haloalkoxy, preferably trifluoro(C₁-C₆)alkyl anddifluoro(C₁-C₆)alkyl, more preferably trifluoro(C₁-C₃)alkoxy anddifluoro(C₁-C₃)alkoxy, most preferably —OCF₃ and —OCHF₂; and —N═CH—R⁷;

each R² is independently selected from the group consisting of —H and—(C₁-C₈)hydrocarbyl, preferably —(C₁-C₆)alkyl, more preferably—(C₁-C₃)alkyl, most preferably —CH₃ or —C₂H₅;

each R³ is independently selected from the group consisting of —H;—(C₁-C₈)hydrocarbyl, preferably —(C₁-C₆)alkyl, more preferably—(C₁-C₃)alkyl, most preferably —CH₃ and —C₂H₅; —O(C₁-C₈)hydrocarbyl,preferably —O(C₁-C₆)alkyl, more preferably —O(C₁-C₃)alkyl, mostpreferably —OCH₃ and —OC₂H₅; substituted and unsubstituted aryl,preferably substituted and unsubstituted phenyl; substitutedheterocyclyl(C₁-C₃)alkyl; heteroaryl(C₁-C₃)alkyl; —(C₂-C₁₀)heteroalkyl;—(C₁-C₆)haloalkyl, preferably trifluoro(C₁-C₆)alkyl ordifluoro(C₁-C₆)alkyl, more preferably trifluoro(C₁-C₃)alkyl anddifluoro(C₁-C₃)alkyl, most preferably —CF₃ and —CHF₂; —CR²R⁴NHR⁵;—N(²)₂, —(C₁-C₃)alkyleneNH₂; —(C₁-C₃)alkylene-N(CH₃)₂;—(C₁-C₃)perfluoroalkylene-N(CH₃)₂; —(C₁-C₃)alkylene-N⁺(C₁-C₃)₃;—(C₁-C₃)alkylene-N⁺(CH₂CH₂OH)₃; —(C₁-C₃)alkylene-OR²;—(C₁-C₄)alkylene-CO₂R²; —(C₁-C₄)alkylene-C(═O)halogen;—(C₁-C₃)alkylene-C(═O)(C₁-C₃)alkyl; and —(C₁-C₄)perfluoroalkylene-CO₂R²;

each R⁴ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —(CH₂)₄—NH₂,—(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃,—CH₂-(3-indolyl), and —CH₂-(4-hydroxyphenyl);

each R⁵ is independently selected from the group consisting of —H and acarboxy terminally linked peptidyl residue containing from 1 to 3 aminoacids in which the terminal amino group of the peptidyl residue ispresent as a functional group selected from the group consisting of—NH₂; —NHC(═O)(C₁-C₆)alkyl; —NH(C₁-C₆)alkyl; —NH(C₁-C₆ alkyl)₂ and—NHC(═O)O(C₁-C₇)hydrocarbyl, preferably —NHC(═O)O(C₁-C₆)alkyl and—NHC(═O)O-benzyl;

each R⁶ is independently selected from the group consisting of —OR² andan N-terminally linked peptidyl residue containing from 1 to 3 aminoacids in which the terminal carboxyl group of the peptidyl residue ispresent as a functional group selected from the group consisting of—CO₂R² and —C(═O)NR² ₂; and

each R⁷ is independently selected from the group consisting ofsubstituted and unsubstituted aryl, preferably substituted andunsubstituted phenyl; and substituted and unsubstituted heteroaryl; or

a salt of such a compound, preferably a pharmaceutically acceptable saltof such a compound.

Substituents on substituted aryl R³ and R⁷, and on substitutedheteroaryl R⁷, are preferably selected from halogen, (C₁-C₈)hydrocarbyl,—NH₂, —NO₂, N-methylpiperazinyl, —OH and —O(C₁-C₈)hydrocarbyl.

Substituents on substituted heterocyclyl(C₁-C₃)alkyl R³ are preferablyselected from —(C₁-C₇)hydrocarbyl, more preferably —(C₁-C₆)alkyl;—C(═O)(C₁-C₆)alkyl, more preferably —C(═O)(C₁-C₃)alkyl, most preferablyacetyl; and —(C₁-C₆)perfluoroalkyl, more preferably—(C₁-C₃)perfluoroalkyl, most preferably —CF₃.

Compounds of Formula IA

According to one embodiment of the compounds of Formula I, there isprovided a compound according to Formula IA:

wherein:

A¹ and B¹ are independently aryl or heteroaryl;

x and y are independently 0, 1, 2, 3, 4 or 5;

each R^(a) is independently selected from the group consisting ofhalogen; —(C₁-C₈)hydrocarbyl, —C(═O)R², —NR² ₂, —NHC(═O)R³, —NHSO₂R³,—NHR⁴, —NHCR²R⁴C(═O)R⁶, —C(═O)OR², —C(═O)NHR²; —NO₂, —CN, —OR²,—P(═O)(OH)₂, dimethylamino(C₂-C₆ alkoxy), —NHC(═NH)NHR²,—(C₁-C₆)haloalkyl, —(C₁-C₆)haloalkoxy and —N═CH—R⁷;

each R^(b) is independently selected from the group consisting of—(C₁-C₈)hydrocarbyl, —C(═O)R², halogen, —NO₂, —CN, —OR², —C(═O)OR², —NR²₂, (C₁-C₆)haloalkyl and (C₁-C₆)haloalkoxy; or

a salt of such a compound, preferably a pharmaceutically acceptable saltof such a compound;

provided that:

the highest value of x or y is equal to the number of substitutablehydrogen atoms in the ring to which x or y is attached; and

when A¹ and B¹ are both phenyl, the sum of x and y is greater than zero.

According to some embodiments of the compounds of Formula IA, the sum ofx and y is greater than zero.

According to other embodiments of the compounds of Formula IA, the sumof x and y is greater than one.

According to yet other embodiments of the compounds of Formula IA, thesum of x and y is greater than two.

According to still other embodiments of the compounds of Formula IA, thesum of x and y is greater than three.

According to some embodiments of the compounds of Formula IA, both x andy are greater than zero.

According to other embodiments of the compounds of Formula IA, both xand y are greater than one.

According to still other embodiments of the compounds of Formula IA,both x and y are greater than two.

A. First Embodiment of Compounds of Formula IA

According to a First Embodiment of the compounds of Formula IA, A¹ is anaryl ring.

Preferred compounds include, for example:(1E)-2-(4-fluorophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(4-chlorophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-4-bromophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(2-nitrophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(3-nitrophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(4-nitrophenyl)-1-[(naphthylmethyl)sulfinyl]ethene; and saltsthereof.

1. Compounds of Formula IB

According to a sub-embodiment of the First Embodiment of the Compoundsof Formula IA, there is provided a compound according to Formula IB:

or a salt thereof.

Preferably, for compounds of Formula IB, each R^(a) is independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —CN, —C(═O)OR², —OH, —NH₂, (C₁-C₆)trifluoroalkoxyand —CF₃.

a. Compounds of Formula IC

According to a sub-embodiment of the compounds according to Formula IB,there is provided a compound according to Formula IC:

or a salt thereof.

Preferably, for compounds of Formula IC, each R^(a) and R^(b) areindependently selected from the group consisting of halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂, —CN and —CF₃.

Preferably, for compounds according to Formula IC, the conformation ofthe substituents on the carbon-carbon double bond is E-.

Preferably for compounds of Formula IC, x and y are independently 0, 1or 2.

Preferably for compounds of Formula IC, n is 1.

Preferably for compounds of Formula IC, R¹ is —H

Preferred compounds according to Formula IC include, for example:(1E)-1-{[(3-amino-4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethane;(1E)-1-{[(3-hydroxy-4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethane;(1E)-1-{[(4-methoxy-3-nitrophenyl)methyl]-sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethane;2-({[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]amino}sulfonyl)aceticacid;2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}aceticacid;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]aminocarboxamidine;2-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]amino}aceticacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](3,5-dinitrophenyl)carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](3,5-diaminophenyl)carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]-2-chloroacetamide;N-[5-({[(1E)-2-2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(4-methylpiperazinyl)acetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]benzamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](4-nitrophenyl)carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](4-aminophenyl)carboxamide;(1E)-1-[({3-[(1Z)-1-aza-2-(4-nitrophenyl)vinyl]-4-methoxyphenyl}methyl)sulfinyl]-2-(2,4,6-trimethoxyphenyl)ethene;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](2R)-2,6-diaminohexanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](2R)-2-amino-3-hydroxypropanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl](2S)-2-amino-3-hydroxypropanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]aminoamide;(1E)-1-({[4-methoxy-3-(methylamino)phenyl]methyl}sulfinyl)-2-(2,4,6-trimethoxyphenyl)ethene;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]acetamide;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl][(2,4-dinitrophenyl)sulfonyl]-amine;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl][(2,4-diaminophenyl)sulfonyl]amine;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(dimethylamino)acetamide;2-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]amino}propanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl][4-(4-methylpiperazinyl)phenyl]carboxamide;N-[5-({[(1E)-2-2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-hydroxyacetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-pyridyl-acetamide;{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]carbamoyl}methylacetate;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-hydroxypropanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(triethylamino)acetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]-2-[tris(2-hydroxyethyl)amino]acetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-hydroxy-2-methylpropanamide;1-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-isopropylacetate;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2,2,2-trifluoroacetamide;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl][(trifluoromethyl)sulfonyl]amine;3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl)carbamoyl}propanoicacid;3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}propanoylchloride;3-[({N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]-carbamoyl}methyl)oxycarbonyl]propanoicacid;4-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-butanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(phosphonooxy)acetamide,disodium salt;4-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]amino}-butanoicacid;3-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]amino}propanoicacid;N-[5({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]methoxycarboxamide;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-[(4-methoxyphenyl)sulfonyl]amine;{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]carbamoyl}ethylacetate;methyl-3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}propanoate;ethyl-2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}acetate;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2,2,3,3,3-pentafluoropropanamide;methyl-2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]carbamoyl}-2,2-difluoroacetate;3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-2,2,3,3-tetrafluoropropanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-aminoacetamide;2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-2,2-difluoroaceticacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(dimethylamino)-2,2-difluoroacetamide,4-((1E)-2-{[(4-fluorophenyl)methyl]sulfinyl}-vinyl)benzoic acid;4-((1E)-2-{[(4-iodophenyl)methyl]sulfinyl}vinyl)benzoic acid;4-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)benzoic acid;1-[5-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)-2-fluoro-phenyl]-2-(dimethylamino)ethan-1-one;(1E)-2-(2,4-difluorophenyl)-1-{[(4-bromophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-amino-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]-sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-2-(4-fluorophenyl)-1-{[(2,3,4,5,6-pentafluorophenyl)-methyl]sulfinyl}ethene;(1E)-2-(4-chlorophenyl)-1-{[(2,3,4,5,6-pentafluorophenyl)-methyl]sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(2,3,4,5,6-pentafluorophenyl)-methyl]sulfinyl}ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(4chlorophenyl)methyl]sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]-sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-methyl-2,4-dimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3,4,5-trimethoxyphenyl)ethene;(1E)-1-{[(2-nitro-4,5-dimethoxyphenyl)methyl]sulfinyl}-2-(3,4,5-trimethoxyphenyl)ethene;(1E)-1-{[(2-nitro-4,5-dimethoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(2-nitro-4,5-dimethoxyphenyl)methyl]-sulfinyl}-2-(3-methyl-2,4-dimethoxyphenyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2,3,4-trifluorophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,3,4-trifluorophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,6-methoxy-4-hydroxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,3,5,6-tetrafluorophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,5-trimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,3,4-trimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-nitro-4-hydroxy-5-methoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3,4-dimethoxy-6-nitrophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3,4-dimethoxy-5-iodophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,6-dimethoxy-4-fluorophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]-sulfinyl}-2-(2-hydroxy-4,6-dimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethylphenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,6-dimethoxy-4-fluorophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-hydroxy-4,6-dimethoxyphenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2,6-dimethoxy-4-fluorophenyl)ethene;(1E)-1-{[(2,4,6-trimethoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(2,3,4-trimethoxyphenyl)methyl]sulfinyl}-2-(2,6-dimethoxyphenyl)ethene;(1E)-1-{[(3,4,5-trimethoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(3,4,5-trimethoxyphenyl)methyl]-sulfinyl}-2-(2,6-dimethoxyphenyl)ethene;(1E)-1-{[(3,4,5-trimethoxyphenyl)methyl]sulfinyl}-2-(4-fluorophenyl)ethene;(1E)-2-(4-fluorophenyl)-1-({[4-(trifluoromethyl)phenyl]methyl}-sulfinyl)ethene;(1E)-2-(4-chlorophenyl)-1-({[4-(trifluoromethyl)phenyl]methyl}-sulfinyl)ethene;(1E)-2-(4-bromophenyl)-1-({[4-(trifluoromethyl)phenyl]methyl}-sulfinyl)ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(4-fluoro-phenyl)ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(4-chloro-phenyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(4-fluoro-phenyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(4-chloro-phenyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(4-bromo-phenyl)ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-nitrophenyl)methyl]sulfinyl}ethene;4-({[(1E)-2-(4-fluorophenyl)vinyl]-sulfinyl}methyl)benzene-carbonitrile;4-({[(1E)-2-(4-chlorophenyl)vinyl]-sulfinyl}methyl)benzene-carbonitrile;4-({[(1E)-2-(4-bromophenyl)vinyl]-sulfinyl}methyl)benzene-carbonitrile;(1E)-2-(3,4-difluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-chloro-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-chloro-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2,3-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-iodophenyl)methyl]-sulfinyl}ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(4-iodophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(4-iodophenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-iodophenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-chlorophenyl)ethene;(1E)-2-(4-bromophenyl)-1-{[(4-iodophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(4-nitrophenyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(2-nitrophenyl)ethene;(1E)-2-(4-iodophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]-sulfinyl}-2-(4-iodophenyl)-ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(2-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(3-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-trifluoromethyl-4-fluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(2-trifluoromethylphenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-trifluoromethylphenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-trifluoromethylphenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-trifluoromethyl-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-methyl-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-trifluoromethyl-4-fluorophenyl)-1-{[(2,4-dichloro-phenyl)methyl]sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-bromo-phenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-trifluoromethylphenyl)-1-{[(4-bromophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-trifluoromethylphenyl)-1-{[(4-bromophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-cyanophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-cyanophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-cyanophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}-ethene;(1E)-2-(4-bromophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}-ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-chlorophenyl)-1-{[(4-methoxyphenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(4-methoxyphenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-chlorophenyl)-1-{[(4-nitrophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-nitrophenyl)methyl]sulfinyl}ethene; andsalts thereof.

(i) First Preferred Sub-Embodiment of Compounds According to Formula IC

According to a one preferred sub-embodiment of the compounds accordingto Formula IC, there is provided a compound wherein:

R^(a) is selected from the group consisting of chlorine, fluorine andbromine, and is bonded to the para position of the ring to which it isattached;

x is 0 or 1;

R^(b) is selected from the group consisting of chlorine, fluorine,bromine, methyl and methoxy, and is bonded to the ortho or para positionof the ring to which it is bonded; and

y is 0, 1, 2 or 3.

Preferably, the conformation of the substituents on the carbon-carbondouble bond is E-.

Compounds according to the above preferred sub-embodiment of compoundsaccording to Formula IC include, for example:(1E)-2-(2-chlorophenyl)-1-[benzylsulfinyl]ethene;(1E)-2-(4-chlorophenyl)-1-[benzylsulfinyl]ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(4-fluorophenyl)-ethene;(1E)-2-(4-chlorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(2,4-difluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-fluorophenyl)-ethene;(1E)-2-(4-bromophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-bromophenyl)methyl]-sulfinyl}-2-(4-chlorophenyl)ethene; andsalts thereof

(ii) Second Preferred Sub-embodiment of Compounds According to FormulaIC

According to a second preferred sub-embodiment of the compounds ofFormula IC, there is provided a compound wherein:

each of R^(a) and R^(b) are independently selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halogen and nitro, and arebonded to the ortho or para position of the ring to which they areattached; and

x and y are independently 0, 1, 2 or 3.

Preferably, for the second preferred sub-embodiment of compoundsaccording to Formula IC, the conformation of the substituents on thecarbon-carbon double bond is Z-.

Preferred compounds according to the second preferred sub-embodiment ofcompounds of Formula IC include, for example:(1Z)-2-phenyl-1-[benzylsulfinyl]ethene;(1Z)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-phenylethene;(1Z)-1-{[(2-chlorophenyl)methyl]sulfinyl}-2-phenylethene;(1Z)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-phenylethene;(1Z)-2-(4-chlorophenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-chlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1Z)-2-(4-chlorophenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}-ethene;(1Z)-2-(4-chlorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1Z)-2-(4-fluorophenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-bromophenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-bromophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-bromophenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-bromophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-methylphenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-methylphenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-methylphenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-methylphenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-{[(4-iodophenyl)methyl]-sulfinyl}ethene; andsalts thereof.

B. Second Embodiment of Compounds of Formula IA

According to a Second Embodiment of the compounds of Formula IA, thereis provided a compound of Formula ID:

wherein B² is selected from the group consisting of heteroaryl and arylother than phenyl; or a salt thereof.

Preferably, B² is selected from the group consisting of furyl, thienyl,pyrrolyl, thiazolyl, pyridyl, thienyl-1-dioxide, anthryl, and naphthyl.

Preferably, for compounds of Formula ID, n is 1.

Preferably, for compounds of Formula ID, R¹ is —H

Preferably, for compounds of Formula ID, R^(a) is independently selectedfrom the group consisting of halogen, (C₁-C₃)alkoxy, —CN, —NO₂, and—CF₃.

Preferably, the conformation of the substituents on the carbon-carbondouble bond is E-.

Preferred compounds according the second sub-embodiment of the compoundsof Formula IA include, for example:(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-pyridyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(3-pyridyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(4-pyridyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-pyridyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(3-pyridyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(4-pyridyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-pyridyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]-sulfinyl}-2-(3-pyridyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-pyridyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-thienyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-thienyl)ethene;(1E)-1-{[4-bromophenyl)methyl]sulfinyl}-2-(2-thienyl)ethene;(1E)-2-(4-bromo(2-thienyl))-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(5-bromo(2-thienyl))-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(5-bromo(2-thienyl))-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(5-bromo(2-thienyl))-1-{[(4-bromophenyl)methyl]-sulfinyl}ethene;2-((1E)-2-{[(4-fluoro-phenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;2-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;2-((1E)-2-{[(4-bromophenyl)methyl]-sulfinyl}vinyl)thiole-1,1-dione;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-methylphenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]-sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-trifluoromethylphenyl)methyl]-sulfinyl}-2-(3-thienyl)-ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(3-thienyl)-ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-cyanophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-nitrophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;3-((1E)-2-{[(4-fluorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(4-bromophenyl)methyl]-sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(4-methoxyphenyl)methyl]-sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(2,4-dichlorophenyl)methyl]-sulfinyl}vinyl)thiole-1,1-dione;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-furyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-furyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-furyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-methylphenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-trifluoromethylphenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]-sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-cyanophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-nitrophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(1,3-thiazol-2-yl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-pyrrol-2-ylethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-pyrrol-2-ylethene;(1E)-1-{[(4-chlorophenyl)methyl]-sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl)-2-naphthylethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-naphthyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-naphthylethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-naphthyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-naphthylethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-naphthyl)ethene;(1E)-2-(9-anthryl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(9-anthryl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(9-anthryl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene; and saltsthereof.

Novel Synthetic Intermediates

The invention is also directed to intermediates, useful in thepreparation of compounds of Formula I. Accordingly, there is provided anintermediate compound according to Formula II:

wherein:

A, n, R¹ and * are as defined herein for compounds of Formula I;

or a salt thereof.

Preferably, for compounds of Formula II, A is other than unsubstitutedphenyl.

The Formula II intermediate may be prepared, for example, by reacting anintermediate of Formula IIA:

wherein A, n, R¹ and * are as defined herein for compounds of Formula I;or a salt thereof;

with an oxidizing agent capable of oxidizing a sulfide to a sulfoxide;and isolating a compound of Formula II from the reaction products.

The Formula IIA compound may be prepared, for example, by reacting acompound of Formula IIB:

wherein:

-   -   L is a leaving group;

with mercaptoacetic acid; and isolating a compound of Formula IIA fromthe reaction products.

According to another embodiment of the invention, there is provided anintermediate compound according to Formula IV, useful for thepreparation of α,β-unsaturated sulfoxides of Formula Iz:

wherein A, B, n, R¹ and * are as defined herein for compounds of FormulaI, and the conformation of the substituents on the two carbons of thecarbon-carbon double bond is E-; or a salt thereof.

Preferably, for compounds of Formula IV, A and B are other thanunsubstituted phenyl.

The Formula IV compound may be prepared, for example, by reacting acompound of Formula IVA.

wherein Q⁺ is a counterion preferably selected from the group consistingof alkali metals, alkaline earth metals and transition metals;

with a compound of Formula IVB:

and isolating a compound of Formula IV from the reaction products.

Processes of Preparing Compounds of Formula I

Processes for preparing compounds according to the present invention areprovided. According to one such embodiment, a compound of Formula Ie:

wherein A, B, R¹ and n are as defined herein;

is prepared by reacting a compound of Formula II:

with a compound of Formula III:

and isolating a compound of Formula Ie from the reaction products.

According to another such embodiment, a compound of Formula Iz isprepared by reacting a compound of Formula IV:

with an oxidizing agent capable of oxidizing a sulfide to a sulfoxide;and isolating a compound of Formula Iz from the reaction products.

Process Wherein a Compound According to Formula I is Employed as aChemical Intermediate

According to another embodiment of the present invention, compoundsaccording to Formula I may be employed as chemical intermediates in thepreparation of an α,β-unsaturated sulfones.

According to such an embodiment, a compound according to Formula V:

wherein A, B, n, R¹, and * are as defined for compounds according toFormula I, and the conformation of the substituents on the carbon-carbondouble bond is either E- or Z-, or a salt thereof; is prepared by thesteps of:

(a) reacting a compound according to Formula I, as defined herein, withat least one oxidizing agent capable of oxidizing a sulfoxide to asulfone; and

(b) isolating a compound according to Formula V from the reactionproducts.

Pharmaceutical Compositions of Compounds of Formula I

According to another embodiment of the invention, pharmaceuticalcompositions are provided, comprising a pharmaceutically acceptablecarrier and a compound according to Formula I:

wherein ring A ring B, R¹, and * are as described above for Formula I;or a salt of such a compound.

In yet another embodiment of the invention, a conjugate of the FormulaI-L-Ab is provided wherein I is a compound of Formula I; Ab is anantibody; and -L- is a single bond or a linking group covalently linkingsaid compound of Formula I to said antibody.

According to sub-embodiments of conjugates thereof, the compound ofFormula I, forming the conjugate is a compound of Formula Ie, Iz or IA.

In a preferred sub-embodiment of the aforesaid conjugates, the antibody(Ab) is a monoclonal antibody or a monospecific polygonal antibody.

In more preferred sub-embodiments of the aforesaid conjugates theantibody (Ab) is a tumor-specific antibody.

Pharmaceutical compositions are provided comprising a pharmaceuticallyacceptable carrier and at least one conjugate according to FormulaI-L-Ab.

In yet a further embodiment of the present invention, there is provideda compound of Formula I derivatized as a substrate for a β-lactamaseenzyme.

Methods of Treatment

According to another embodiment of the invention, there is provided amethod of treating an individual for a proliferative disorder,particularly cancer, comprising administering to the individual aneffective amount of at least one compound of Formula I or at least oneconjugate of Formula I-L-Ab, alone or in combination with apharmaceutically acceptable carrier.

According to a further embodiment of the invention, a method of inducingapoptosis of tumor cells in an individual afflicted with cancer isprovided, comprising administering to the individual an effective amountof at least one compound of Formula I, or at least one conjugate ofFormula I-L-Ab, either alone or in combination with a pharmaceuticallyacceptable carrier.

According to another embodiment of the invention, a method of inhibitingthe growth of tumor cells in an individual afflicted with cancer isprovided, comprising administering to the individual an effective amountof at least one compound of Formula I, or at least one conjugate of theFormula I-L-Ab, alone or in combination with a pharmaceuticallyacceptable carrier.

According to another embodiment of the invention, a method of reducingor eliminating the effects of ionizing radiation on normal calls in anindividual who has incurred or is at risk for incurring exposure toionizing radiation, is provided. This method comprises administering tothe individual either prior to, or after the exposure to ionizingradiation, at least one compound of Formula I, alone or in combinationwith a pharmaceutically acceptable carrier.

According to another embodiment of the invention, there is provided amethod of safely increasing the dosage of therapeutic ionizing radiationused in the treatment of cancer or another proliferative disorder,comprising administering an effective amount of at least oneradioprotective compound of Formula I, alone or in combination with apharmaceutically acceptable carrier. This radioprotective compoundinduces a temporary radioresistant phenotype in the normal tissue of theindividual.

According to another embodiment of the invention, there is provided amethod for treating an individual who has incurred, or is at risk forincurring, remediable radiation damage from exposure to ionizingradiation. This method comprises administering an effective amount of atleast one radioprotective compound of Formula I, alone or in combinationwith a pharmaceutically acceptable carrier, either prior to, or afterthe individual incurs remediable radiation damage from exposure toionizing radiation.

According to other embodiments of the invention, there is provided theuse of at least one compound according to Formula I, or at least oneconjugate according to Formula I-L-Ab, either alone or as a part of apharmaceutical composition, for preparation of a medicament for:

(a) treating a proliferative disorder in an individual afflicted with aproliferative disorder;

(b) inhibiting the growth of tumor cells in an individual afflicted withcancer;

(c) inducing apoptosis of tumor cells in an individual afflicted withcancer;

(d) treating an individual who has incurred, or is at risk for incurringremediable radiation damage from exposure to ionizing radiation;

(e) reducing or eliminating the effects of ionizing radiation on normalcalls in an individual who has incurred or is at risk for incurringexposure to ionizing radiation;

(f) safely increasing the dosage of therapeutic ionizing radiation usedin the treatment of cancer or another proliferative disorder; or

(g) protecting an individual from cytotoxic side effects of theadministration of a cytotoxic agent.

According to another embodiment of the invention, there is provided amethod of treating an individual for a proliferative disorder,particularly cancer, comprising:

-   -   (1) administering to the individual an effective amount of at        least one radioprotective compound of Formula I, or at least one        conjugate of Formula I-L-Ab; and    -   (2) administering an effective amount of therapeutic ionizing        radiation.

According to another embodiment of the invention, there is provided amethod of reducing the number of malignant cells in the bone marrow ofan individual, comprising

-   -   (1) removing a portion of the individual's bone marrow,    -   (2) administering an effective amount of at least one        radioprotective compound of Formula I, to the removed bone        marrow; and    -   (3) irradiating the removed bone marrow with an effective amount        of ionizing radiation.

In one sub-embodiment of the above method of reducing the number ofmalignant cells in the bone marrow of an individual, the method furthercomprises the step of replacing the removed bone marrow with theirradiated bone marrow.

According to another embodiment of the invention, there is provided amethod for protecting an individual from cytotoxic side effects of theadministration of a cytotoxic agent, particularly a mitotic phase cellcycle inhibitor or a topoisomerase inhibitor, comprising administeringto the individual, in advance of the administration of the cytotoxicagent, an effective amount of at least one cytoprotective compound ofFormula I; wherein the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor is not a compound of Formula I.

Mitotic cell phase inhibitors include, but are not limited to vincaalkaloids, e.g., vincristine and vinblastine, particularly vincristine;taxanes, e.g., paclitaxel and analogs of paclitaxel, particularlypaclitaxel; naturally occurring macrolides, e.g., rhizoxin, maytansine,ansamitocin P-3, phomopsin A, dolastatin 10 and halichrondin B;colchicine and derivatives of colchicine.

Paclitaxel is an anti-mitotic drug presently used as an initialtreatment for ovarian, breast and lung cancer, with moderate success.Vincrisitin is a well-established anti-mitotic drug widely used for thetreatment of breast cancer, Hodgkin's lymphoma and childhood cancers.

Topoisomerase inhibitors may be inhibitors of topoisomerase I,topoisomerase II or both. Topoisomerase I inhibitors include, but arenot limited to, adriamycin and etoposide. Topoisomerase II inhibitorsinclude, but are not limited to, camptothecin, irinotecan, topotecan andmitoxanthrone.

According to another embodiment of the invention, there is provided amethod of treating an individual for a proliferative disorder,particularly cancer, comprising:

-   -   (1) administering to the individual an effective amount of at        least one cytoprotective compound of Formula I, or at least one        conjugate of Formula I-L-Ab;, and    -   (2) administering an effective amount of at least one mitotic        cell phase inhibitor or topoisomerase inhibitor after        administration of the at least one cytoprotective compound of        Formula I, or at least one conjugate of Formula I-L-Ab;.

DETAILED DESCRIPTION OF THE INVENTION

Treatment of Proliferative Disorders

According to the present invention, α,β-unsaturated sulfoxides and saltsthereof are believed to selectively inhibit proliferation of cancercells, and kill various tumor cell types without killing (or withreduced killing of) normal cells. It is believed that cells are killedat concentrations where normal cells may be temporarily growth-arrestedbut not killed.

The compounds of the invention may be administered to individuals(mammals, including animals and humans) afflicted with cancer.

The compounds of the invention are believed to inhibit the proliferationof tumor cells and, for some compounds, to induce cell death. Cell deathis believed to result from the induction of apoptosis. The compounds arebelieved effective against a broad range of tumor types, including butnot limited to the following: ovarian cancer; cervical cancer; breastcancer; prostate cancer; testicular cancer, lung cancer, renal cancer;colorectal cancer; skin cancer; brain cancer; leukemia, including acutemyeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, andchronic lymphoid leukemia.

More particularly, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto:

Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

Lung: bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma;

Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma);

Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma);

Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors;

Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma);

Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma[embryonal rhabdomyosarcoma], fallopian tubes (carcinoma);

Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'slymphoma, non-Hodgkin's lymphoma [malignant lymphoma] and Waldenström'smacroglobulinemia;

Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell” as provided herein, includes a cell afflicted by any one ofthe above identified disorders.

The compounds are also believed useful in the treatrnent of non-cancerproliferative disorders, that is, proliferative disorders which arecharacterized by benign indications. Such disorders may also be known as“cytoproliferative” or “hyperproliferative” in that cells are made bythe body at an atypically elevated rate. Non-cancer proliferativedisorders believed treatable by compounds of the invention include, forexample: hemangiomatosis in newborn, secondary progressive multiplesclerosis, atherosclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, uterinefibroids, Peronies and Duputren's fibrosis, restenosis, benignproliferative breast disease, benign prostatic hyperplasia, X-linkedlymphoproliferative disorder (Duncan disease), post-transplantationlymphoproliferative disorder (PTLD), macular degeneration, andretinopathies such as diabetic retinopathies and proliferativevitreoretinopathy (PVR)

Other non-cancer proliferative disorders believed treatable by compoundsof the invention include pre-cancerous lymphoproliferative cellsassociated with an elevated risk of progression to a cancerous disorder.Many non-cancerous lymphoproliferative disorders are associated withlatent viral infections such as Epstein-Barr virus (EBV) and HepatitisC. These disorders often begin as a benign pathology and progress intolymphoid neoplasia as a function of time.

Treatment of tumor cells with the α,β-unsaturated sulfoxide compounds ofthe invention is believed to lead to inhibition of cell proliferationand induction of apoptotic cell death.

Radioprotective Treatment

The compounds of the invention are also believed to protect normal cellsand tissues from the effects of acute and chronic exposure to ionizingradiation.

Individuals may be exposed to ionizing radiation when undergoingtherapeutic irradiation for the treatment of proliferative disorders.The compounds are believed effective in protecting normal cells duringtherapeutic irradiation of abnormal tissues. The compounds are alsobelieved useful in protecting normal cells during radiation treatmentfor leukemia, especially in the purging of malignant cells fromautologous bone marrow grafts with ionizing radiation.

According to the invention, therapeutic ionizing radiation may beadministered to an individual on any schedule and in any dose consistentwith the prescribed course of treatment, as long as the radioprotectantcompound of the invention is administered prior to the radiation. Thecourse of treatment differs from individual to individual, and those ofordinary skill in the art can readily determine the appropriate dose andschedule of therapeutic radiation in a given clinical situation.

Chemoprotective Treatment

In addition, the compounds of the present invention are believed toprotect normal cells and tissues from the effects of exposure tocytotoxic agents such as for example, mitotic phase cell cycleinhibitors and topoisomerase inhibitors.

Mitotic Phase Cell Cycle Inhibitors

The usual description of the cell cycle describes the cycle in terms ofa series of phases—interphase and M (mitotic) phase—and the subdivisionof interphase into the times when DNA synthesis is proceeding, known asthe S-phase (for synthesis phase), and the gaps that separate theS-phase from mitosis. G1 is the gap after mitosis but before DNAsynthesis starts, and G2 is the gap after DNA synthesis is completebefore mitosis and cell division. Interphase is thus composed ofsuccessive G1, S and G2 phases, and normally comprises 90% or more ofthe total cell cycle time. The M phase consists of nuclear division(mitosis) and cytoplasmic division (cytokinesis). During the early partof the M phase, the replicated chromosomes condense from their extendedinterphase condition. The nuclear envelope breaks down, and eachchromosome undergoes movements that result in the separation of pairs ofsister chromatids as the nuclear contents are divided. Two new nuclearenvelopes then form, and the cytoplasm divides to generate two daughtercells, each with a single nucleus. This process of cytokinesisterminates the M phase and marks the beginning of the interphase of thenext cell cycle. The daughter cells resulting from completion of the Mphase begin the interphase of a new cycle.

A mitotic phase cell cycle inhibitor is a chemical agent whose mechanismof action includes inhibition of a cell's passage through any portion ofthe mitotic (M) phase of the cell cycle. Such agents include, by way ofexample and not limitation, taxanes, such as paclitaxel and its analogs;vinca alkaloids such as vincristine and vinblastine; colchicine;estramustine; and naturally occurring macrolides such as rhizoxin,maytansine, ansamitocin P-3, phomopsin A, dolastatin 10 and halichrondinB.

Paclitaxel is an anti-mitotic drug presently used as an initialtreatment for ovarian, breast and lung cancer, with moderate success.Vincristine is a well-established anti-mitotic drug widely used for thetreatment of breast cancer, Hodgkin's lymphoma and childhood cancers.

Topoisomerase Inhibitors

A topoisomerase inhibitor is a chemical agent whose mechanism of actionincludes interfering with the function of a topoisomerase.

The topoisomerases constitute a group of enzymes that catalyze theconversion of DNA from one topological form to another by introducingtransient breaks in one or both strands of a DNA duplex. Topologicalisomers are molecules that differ only in their state of supercoiling.Topoisomerases serve to relieve torsional stress during replication andtranscription. They alter the DNA structure, but not the sequence.

Three different types of topoisomerases have been reported in humans.They are topoisomerase I (91 kDa monomer), and topoisomerase II, whichis further subclassified as IIα (170 kDa dimer), and IIβ (180 kDadimer). The three different types are encoded by genes on three separatechromosomes. Simpler organisms possess only topoisomerase I; however,higher organisms have all three types of topoisomerases. Whiletopoisomerase IIα is present in all eukaryotes, IIβ is present only invertebrates and appears to be more closely associated with celldifferentiation than proliferation. Topoisomerase IIβ appears to behighly homologous to the type IIα.

Topoisomerases act by catalyzing the breakdown and rejoining reactionsin the phosphodiester backbone of the DNA molecules. Topoisomerase Ireversibly cleaves a single strand in duplex DNA molecule, whereastopoisomerase II breaks and rejoins both DNA strands. These reactionsare believed to proceed via transient reaction intermediates, known as“cleavable complexes,” where the enzymes (or enzyme subunits) formcovalent bonds involving a tyrosine and the cleaved phosphodiester bondof the DNA substrate backbone.

Topoisomerases have become important chemotherapeutic targets for cancertreatment. Camptothecin and its derivatives are reported to actspecifically at the level of the topoisomerase I—DNA complex andstimulate DNA cleavage. Agents, such as β-lapachone, act by blocking theformation of the topoisomerase I—DNA complex. Several novel compoundshave been developed that can target either topoisomerase I ortopoisomerase IIa-/IIβ-isoforms, or all three types of topoisomerases.Inhibition of topoisomerase II is considered to be more challenging dueto the complexity of interactions. Most inhibitors of topoisomerase IIblock the ligation step, leading to stabilized “cleavable complexes”between DNA and the enzyme. Most enzyme inhibitors function by dockinginto the enzyme active site or nearby allosteric site to block thereaction of the normal substrate. Inhibition of the topoisomerase IIinvolves two parts: the aromatic part of the inhibitor moleculeintercalates between DNA base pairs and another more polar portioninteracts with topoisomerase. Because topoisomerase II inhibitors (e.g.,doxorubicin, and etoposide) act as poisons rather than as classicalcompetitive inhibitors, their action is dependent upon the level of theenzyme in cells. Rapidly proliferating cells, which contain relativelyhigher levels of topoisomerase II, appear to be more sensitive to theseagents. On the other hand, differentiated cells have relatively lowtopoisomerase II levels and are much more resistant to the action ofthese inhibitors.

Inhibitors of topoisomerase I include, for example, adriamycin,etoposide, β-lapachone (Calbiochem No. 428022), AG-555 (Calbiochem No.112270), 10-hydroxycamptothecin (Calbiochem No. 390238), AG-1387(Calbiochem No. 658520), rebeccamycin (Calbiochem No. 553700),nogalamycin (Calbiochem No. 488200), and topotecan (Calbiochem No.614800).

Inhibitors of topoisomerase II include, for example, camptothecin,irinotecan and topotecan, amsacrine (Calbiochem No. 171350),aurintricarboxylic acid (Calbiochem No. 189400), bruneomycin (CalbiochemNo. 571120), ellipticine (Calbiochem No. 324688), epirubicin (CalbiochemNo. 324905), etoposide (Calbiochem No. 341205), genistein (CalbiochemNo. 345834), and merbarone (Calbiochem No. 445800).

Inhibitors of topoisomerase I and II include, for example, aclarubicin(Calbiochem No. 112270), congocidine (Calbiochem No. 480676), daunomycin(Calbiochem No. 251800), ellagic acid (Calbiochem No. 324683), andsuramin (Calbiochem No. 574625).

α,β-UNSATURATED SULFOXIDES OF THE INVENTION

The compounds of the present invention differ from other knowncytoprotective agents in that they are believed to not only protectnormal cells, but also to be operationally cytotoxic in tumor cells. Innormal cells, the cytoprotective compounds of the invention are believedto induce a reversible resting state rendering the normal cellsrelatively refractory to the cytotoxic effect of mitotic phase cellcycle inhibitors and topoisomerase inhibitors.

In addition, without wishing to be bound by any theory, the sulfoxidesof the present invention may be metabolized to active metabolites, suchmetabolism including, but not limited to, oxidation of the sulfoxidemoiety to a sulfone. The biological activity of α,β-unsaturated sulfonesincluding antiproliferative activity, radioprotection activity andchemoprotectant activity is described in U.S. Pat. Nos. 6,201154,6,359,013, 6,414,034, 6,486210, 6,541,475, 6,548,553, 6,576,675,6,599,932, and PCT publications: WO 02069892A3, WO 03064616A2, WO03072062A2 and WO 03072063A2, the entire contents of which areincorporated herein by reference.

The ring systems A and B of the compounds of the invention areoptionally substituted. Any degree of substitution is possible on thering systems A and B of Formula I. The aryl and heteroaryl rings A and Bare preferably mono-, di- or tri substituted, but may be fullysubstituted, i.e., wherein every ring hydrogen atom on A and B isreplaced with a substituent.

The pattern of substitution for ring hydrogens of A and B of Formula Imay comprise any pattern of substitution. For example, on a phenyl A orB ring, tri-substitution may comprise substitution at positions 2, 3 and4, positions 2, 4 and 5, positions 3, 4 and 5, positions 2, 5 an 6 orpositions 2, 4 and 6. Likewise, the pattern of tetra-substitution of aphenyl A or B ring may comprise, for example, substitution at positions2, 3, 4 and 5, positions 2, 4, 5 and 6, or positions 2, 3, 5 and 6.Di-substitution of a phenyl A or B ring may comprise substitution, forexample, at the 2 and 3 positions, the 2 and 4 positions, the 2 and 5positions, the 2 and 6, positions, the 3 and 4 positions, the 3 and 5positions, or the 3 and 6 positions.

The pattern of substitution on a five-membered heteroaryl A or B ringmust also account for the number of heteroatoms contained in theheteroaromatic ring and point of attachment of the heteroaryl ring.Substitution on a five membered heteroaromatic ring containing oneheteroatom, wherein the heteroaryl ring is bonded via its two positionserves to exemplify the variety of substitution patterns. Substitutionon the aforesaid five-membered heteroaryl ring may be, for example, atthe 3, 4 or 5 position for mono-substitution; and at the 3 and 4, the 3and 5, or the 4 and 5 positions for di-substitution.

Where a phenyl A or B ring is mono-substituted the substituent ispreferably located at the ortho- or para-position. Where a phenyl A or Bring is di-substituted, the substituents are preferably located at theortho- and para-positions, or the meta- and para-positions.

According to certain preferred embodiments, the meta- and para-positionof the aryl or heteroaryl A ring of Formula I is substituted.Preferably, the para substituent is halogen or (C₁-C₆)alkoxy, and themeta substituent is amino, alkyl amino, acyl amino or sulfonyl amino inthese embodiments

Besides the terms “para-”, “meta-” and “ortho-”, substitution positionson a ring may be denoted by a numbering system. However numberingsystems are often not consistent between different ring systems. Insix-membered aromatic systems, the spatial arrangements are specified asdescribed above by the common nomenclature “para” for 1,4-substitution,“meta” for 1,3-substitution and “ortho” for 1,2-substitution as shownbelow in Scheme 3.

Since aromatic rings are essentially planar, these designationsessentially define geometric positions on a six-membered ring that couldbe communicated geometrically, i.e., the ortho substituent forms aplanar angle of 60° with a reference substituent to which it is referredto as being ortho. Likewise, a meta substituent defines a 120° planarangle and a para substituent defines a 180° angle.

To designate substituent patterns in a general way for any planar ringsystem, the ortho-meta-para nomenclature is only descriptive forsix-membered monocycles, i.e., there is no “para” substituent on afive-membered aromatic ring or a bicyclic ring. However, definition of aplanar angle or a range of planar angles between two substituents is aconvention which readily communicates a particular substitution patternthat is independent of the nature of the particular ring involved. Thus,a para substituent in a six-membered aromatic ring is closelyapproximated in other planar mono- or bicyclic rings by any substituentwhich, with the reference substituent, forms a planar angle of betweenabout 144° and about 180°. Likewise, a meta substituent in asix-membered aromatic ring is approximated in other planar mono- orbicyclic rings by any substituent which, with the reference substituent,forms a planar angle of between about 90° and about 144°. Severalexamples of substituent patterns which could be communicated in this wayare depicted in Scheme 4.

In some instances, a true angle is not formed between a substituent anda reference substituent. One example of this is a naphthalene systemsubstituted at the 1- and 5-positions as shown in the (e) structureabove. In the (e) structure there is no geometric intersection betweenthe lines defined by the 1- and 5-position bonds. However, it isreasonable to regard these “parallel” bonds as defining a 180° angle andthus approximating the para-arrangement of a six-membered planar ring.

PREPARATION OF COMPOUNDS OF THE INVENTION

α,β-unsaturated sulfoxides of Formula I may be prepared via syntheticorganic chemistry methods within the capability of a chemist of ordinaryskill. Compounds of Formula Ie and of Formula Iz are preferably preparedvia procedures that are selective for the preparation of (E)- or(Z)-olefins respectively.

PREPARATION OF (E)-COMPOUNDS OF THE INVENTION

One preferred preparation of the (E)-α,β-unsaturated sulfoxides ofFormula Ie is by a Knoevenagel condensation of B-aldehydes (iv) withA-(CHR¹)_(n)-sulfinyl acetic acids (iii), according to the Scheme 5below, wherein A, B, n and R¹ are defined as for Formula I, above.

According to Scheme 5, the A-(CHR¹)_(n)-sulfide acetic acid (ii) (forcompounds wherein n is 1) is formed by the reaction of suitable salt ofthioglycollic acid and a A-(CHR¹)_(n)-L compound (i), wherein A, n andR¹ are as defined herein and L is a suitable leaving group. Suitablethioglycollate salts include alkali metal salts such as sodium andpotassium salts. Suitable leaving groups for (i) include, for example,halogen, tosyl, nosyl, trifyl, or mesyl. The reaction is preferablycarried out in a polar solvent, more preferably a (C₁-C₄) alkyl alcohol,e.g., methanol. The reaction is preferably carried out at higher thanambient temperature, more preferably greater than 50° C., mostpreferably at the reflux temperature of the solvent.

For compounds of formula (ii) in Scheme 5 wherein n is zero, thecorresponding aryl or heteroaryl sulfide acetic acid may be prepared byaddition of a copper salt of thioglycollic acid ester, wherein R is analkyl group, preferably (C₁-C₆)alkyl, more preferably, methyl, ethyl ort-butyl, to an intermediate of formula (i) wherein n is 1. The reactionis preferably performed in a basic solvent such as, for examplepyridine, quinoline or lutidine or a polar aprotic solvent such, forexample, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetraglyme,N-methylpyrrolidinone (NMP) or hexamethylphosphoramide (HMPA) at anelevated temperature, preferably greater than 50° C., more preferablygreater than 100° C.

Alternatively, for compounds of formula (ii) in Scheme 5 wherein n iszero, the corresponding aryl or heteroaryl sulfide acetic acid may beprepared by addition of a thioglycollic acid ester, preferably a(C₁-C₆)alkyl ester, more preferably, a methyl, ethyl or t-butyl ester,to an intermediate of formula (i) wherein n is zero and L is a halogen,preferably chlorine or bromine. The reaction may be catalyzed by a zerovalent palladium or nickel catalyst, preferably an air-stable palladiumcatalyst, more preferably dihydrogendichloro-bis-(di-tert-butylphosphinito(P)dipalladate(2-) [391663-95-7]or dihydrogendi-p-chloro-tetrakis-di-tert-butylphosphinito(P)dipalladate(2-)[391708-31-8]. The reaction is done in the presence of a suitable base,preferably sodium-tert-butoxide. The reaction is preferably done in thepresence of a suitable solvent, preferably a solvent having a boilingpoint greater than 50° C., more preferably a solvent selected from thegroup consisting of toluene, xylene, mesitylene, DMF, NMP, and THF. See,Li et al., J. Org. Chem., 2001, 66, 8677-8681; and Li et al., J. Org.Chem., 2002, 67, 3643-3650, the entire disclosures of which areincorporated herein by reference.

The sulfide acetic acid compound (ii) in Scheme 5 may be then oxidizedwith a suitable oxidizing agent to give a corresponding sulfinyl aceticacid compound (iii). A suitable oxidizing agent is any oxidant capableof selectively oxidizing a sulfide to a sulfoxide. Examples include3-chloroperbenzoic acid (MCPBA) (Aldrich 27,303-1) and potassiumperoxymonosulfate (Aldrich 22,803-6) The oxidation is preferablyperformed at low temperature, preferably from −40° C. to 0° C. Thereaction is preferably carried out in a suitable solvent. Suitablesolvents are preferably nonpolar organic solvents, more preferablyhalogenated solvents, e.g., dichloromethane (DCM).

Condensation of (iii) with the B-aldehydes (iv) via a Knoevenagelreaction in the presence of benzylamine and glacial acetic acid yieldsthe desired (E)-α,β-unsaturated sulfoxide of Formula Ie.

The following is a more detailed two-part synthesis procedure forpreparing the Formula Ie α,β-unsaturated sulfoxides,(E)-A-CHR¹SOCH═CH—B, according to the above Scheme 5 via intermediatesulfonylacetic acid (iii). The following synthesis procedures showsyntheses of compounds wherein A and B are both phenyl. However theprocedures are exemplary of compounds of Formula I comprising other aryland heteroaryl A and B rings.General Procedure 1: Synthesis (E)-α,β Unsaturated Sulfoxides Step A.Synthesis of Substituted benzylthioacetic Acid:

According to Scheme 6, to a cold (0° C.) solution of sodium hydroxide(40 g, 1 mol) in methanol (500 mL), is added thioglycollic acid (46 g,0.5 mol) slowly over 30 minutes. The precipitated sodium thioglycollateformed thereby is dissolved by stirring and warming the reaction mixtureto about 50° C. The solution is then cooled to room temperature. Asubstituted benzyl chloride 1 (80.5 g, 0.5 mol) is added portionwise inorder to attenuate of exothermic nature of the reaction. The resultingreaction mixture is then heated at reflux for 2 hours, then cooled toambient temperature and poured onto crushed ice (1 Kg) containingconcentrated hydrochloric acid (100 mL). A solid white precipitate isformed. The precipitate is filtered, washed with ice cold water anddried under vacuum to yield a benzylthioacetic acid 2.

According to an alternative to step A above, the benzylthioacetic acidintermediates 2 may be generated via the two-step route shown in Scheme6, by substituting a thioglycollate ester (HS—CH₂.CO₂R) forthioglycollic acid, wherein R is an alkyl group, typically (C₁-C₆)alkyl.Reaction of this ester reagent results in the formation of analkylthioacetate intermediate which may be subsequently hydrolyzed toyield the corresponding benzylthioacetic acid 2.Step B. Synthesis of Substituted benzylsulfinylacetic Acid 3:

According to Scheme 7, to a cooled solution of a benzylthioacetic acid 2(10 mmol) in anhydrous dichloromethane (DCM) (15 mL) is added MCPBA (20mmol, 50% concentration basis, Lancaster). The reaction mixture isstirred at about −5° C. for 6 hours. The precipitated 3-chlorobenzoicacid is removed by filtration. The filtrate is washed with water, driedover magnesium sulfate and concentrated. After removal of the solvent,the substituted benzylsulfinylacetic acid 3 is purified either bycrystallization or by silica gel chromatography.Step C. Synthesis of (E)-Substituted styrylbenzyl Sulfoxides 5:

According to Scheme 8, a solution of the substitutedbenzylsulfinylacetic acid 3 (20 mmol) in glacial acetic acid (20 mL) istreated with a substituted benzaldehyde 4 (20 mmol) in the presence of acatalytic amount of benzylamine (0.5 mL). The resulting reaction mixtureis heated at reflux for 6 hours and then cooled to ambient temperature.After cooling, ether (100 mL) is added to the reaction mixture. Theresulting mixture is washed successively with saturated aqueous sodiumhydrogen carbonate (3×30 mL), sodium bisulfite (40 mL), dilutehydrochloric acid (40 mL) and water (60 mL). The ether layer is thendried over anhydrous calcium chloride and concentrated. The resultingsolid residue is purified by crystallization or by column chromatographyon silica gel to yield an (E)-α,β-unsaturated Sulfoxides of Formula Ie,5.Preparation of (Z)-α,β-Unsaturated Sulfoxides of Formula Iz

According to Scheme 9, the (Z)-α,β-unsaturated sulfoxides of Formula Izare preferably prepared by a nucleophilic addition of an appropriatethiol salt (v) to an optionally substituted aryl or heteroarylacetylene(vi), according to the Scheme 9 below. A, B, n and R¹ are defined as forFormula 1, above, and Q⁺ is a counterion, preferably an alkali metal,e.g., sodium, lithium or potassium, an alkaline earth metal, e.g.,calcium or magnesium, or a transition metal, e.g., zinc or copper. Theprocedure is analogous to the procedure described by Reddy et al.,Sulfur Letters 13:83-90 (1991) for the production of (Z)-styrylbenzylsulfoxides. The entire disclosure of Reddy et al. is incorporatedherein by reference.

The sulfide intermediate (vii) is then oxidized by a suitable oxidizingagent. A suitable oxidizing agent is one capable of oxidizing a sulfideto a sulfoxide of Formula Iz. Suitable oxidizing agents for thisreaction are as described above for the oxidation of sulfide aceticacids (ii) to sulfoxide acetic acids (iii) in the preparation of (E)-α,βunsaturated sulfoxides.

The following is a more detailed two-part synthesis for preparing theFormula Iz α,β-unsaturated sulfoxides, (Z)-A-CHR¹SOCH═CH—B. Theprocedure is illustrated where A and B are both phenyl. However theprocedure is applicable to the preparation of compounds of Formula Icomprising other aryl and heteroaryl A and B rings.General Procedure 2: Synthesis (Z)-α,β Unsaturated Sulfoxides Step A.Preparation of the Intermediate Sulfide

According to Scheme 10, to a refluxing methanolic solution of asubstituted or unsubstituted sodium benzylthiolate 6 prepared from 460mg (0.02 g atom) of (i) sodium, (ii) substituted or unsubstituted benzylmercaptan (0.02 mol) and (iii) 80 mL of absolute methanol, is addedfreshly distilled substituted or unsubstituted phenylacetylene 7. Theresulting mixture is heated at reflux temperature for 20 hours, thencooled to ambient temperature and poured onto crushed ice. The resultingcrude product is filtered, dried and recrystallized from methanol oraqueous methanol to yield a pure (Z)-styryl benzylsulfide 8.Step B. Oxidation of the Sulfide 8 to the Corresponding Sulfoxide ofFormula Iz

According to Scheme 11, to a cooled solution (−5 to −10° C.) of the(Z)-α,β-unsaturated sulfide 8 (3.0 g) in anhydrous DCM (30 mL) is addedMCPBA (20 mmol, 50% concentration basis, Lancaster). The reactionmixture is stirred at −5° C. for 6 hours. The precipitated3-chlorobenzoic acid is removed by filtration. The filtrate is washedwith water, dried over magnesium sulfate and concentrated. After removalof the solvent, the product (Z)-α,β-unsaturated sulfoxide of Formula Iis purified either by crystallization or silica gel chromatography.

α,β-Unsaturated Sulfoxides as Intermediates in Preparing α,β-UnsaturatedSulfones

Compounds of the invention may be employed as novel intermediates in thesynthesis of α,β-unsaturated sulfones as shown in Scheme 12.

According to Scheme 12, an α,β-unsaturated sulfoxide, according toFormula I may be oxidized to the corresponding sulfone according toFormula V by use of any reagent capable of oxidizing a sulfoxide to asulfone. Suitable oxidizing reagents include peroxides such as hydrogenperoxide, peracids such as meta-chloroperoxybenzoic acid (MCPBA) orpersulfates such as OXONE (potassium peroxymonosulfate). The reaction ispreferably carried out in the presence of a suitable solvent. Suitablesolvents include, for example, water, acetic acid or non-polar solventssuch as dichloromethane (DCM). The reaction may be performed at elevatedtemperature, for example, from about 30 to about 100° C. with 30%hydrogen peroxide (0.12 mol) in glacial acetic acid (25 mL) by refluxingfor 1-2 hours. When the reaction is complete, the reaction mixture maybe cooled to ambient temperature and poured onto crushed ice. Theproduct may precipitate and subsequently be collected by filtration andrecrystallized from a suitable solvent. Suitable solvents include waterand mixtures of water with one or more water-miscible organic solventssuch as THF, acetone, methanol, ethanol, isopropanol and acetonitrile.

DERIVATIZATION OF COMPOUNDS OF THE INVENTION TO FORM CONJUGATES

Preferably, the derivative comprises a carboxylic acid derivative. Thecarrier may comprise any molecule sufficiently large to be capable ofgenerating an immune response in an appropriate host animal. One suchpreferred carrier is keyhole limpet haemocyanin (KLH). Additionally,structural components of substituents on the A or B rings of compoundsof the invention (e.g., as peptidyl substituents) can potentiallyprovide antigenic activity sufficient to raise antibodies to the styrylsulfones. Antibodies, preferably monoclonal antibodies and monospecificpolyclonal antibodies, and most preferably tumor-specific antibodies maybe covalently linked to compounds of the present invention.

The covalent linker between a compound of Formula I (or Formulae Ie, Izor IA) and an antibody may, in its simplest form, comprise a singlecovalent bond connecting the compound of Formula I to the antibody. Morecommonly, the compound of Formula I is attached to the antibody using asuitable bifunctional linking reagent. The term “bifunctional linkingreagent” refers generally to a molecule that comprises two reactivemoieties which are connected by a spacer element. The term “reactivemoieties” in this context, refers to chemical functional groups capableof coupling with an antibody or a compound of Formula I by reacting withfunctional groups on the antibody and the compound of Formula I.

An example of a covalent bond formed as a linker between a compound ofFormula I and an antibody is a disulfide bond formed by the oxidation ofan antibody and a compound of Formula I, wherein a substituent on A or Bof Formula I comprises a peptidyl moiety containing one or more cysteineamino acids. The cysteine residues can be oxidized to form disulfidelinks by dissolving 1 mg of the a suitable compound of Formula I and 0.5equivalents of the desired antibody in 1.5 mL of 0.1% (v/v) 17.5 mMacetic acid, pH 8.4, followed by flushing with nitrogen and then 0.01 MK₂Fe(CN)₆. After incubation for one hour at room temperature, the adductpeptide is purified by HPLC.

Another example of a suitable covalent bond formed as a linker between acompound of Formula I and an antibody is an amide bond formed byreacting an amino group on a compound of the invention with a carboxylicacid group which forms part of the primary structure of the antibody(Ab) (e.g., for example a glutamic or aspartic amino acid residue).Alternately, an amide bond could be formed if the reacting moieties werereversed, i.e., the compound of Formula I could contain a carboxylicacid functionality and react with an amino functionality within the Abstructure.

Alternatively, a compound of Formula I and an antibody Ab may becovalently linked using a bifunctional linking reagent. In one suchembodiment of the present invention, a compound of Formula I, wherein asubstituent on A or B of Formula I comprises a peptidyl moiety, iscoupled to an antibody using a bifunctional linking reagent.

For example, adducts can be prepared by first preparingS—(—N-hexylsuccinimido)-modified derivatives of an antibody and of acompound of Formula I, according to the method of Cheronis et al., J.Med. Chem. 37: 348 (1994) (the entire disclosure of which isincorporated herein by reference). N-hexylmaleimide, a precursor for themodified antibody and compound of Formula I, is prepared fromN-(methoxycarbonyl)maleimide and N-hexylamine by mixing the twocompounds in saturated NaHCO₃ at 0° C. according to the procedure ofBodanszky and Bodanszky, The Practice of Peptide Synthesis;Springer-Verlag, New York, pp. 29-31 (1984) (the entire disclosure ofwhich is incorporated herein by reference). The product of the resultingreaction mixture is isolated by extraction into ethyl acetate, followedby washing with water, dried over Na₂SO₄, and is then concentrated invacuo to produce N-hexylmaleimide as a light yellow oil.S—(N-hexylsuccinimido)-modified antibody and Formula I compound are thenprepared from a cysteine-containing peptide and N-hexylmaleimide bymixing one part peptide with 1.5 parts N-hexylmaleimide in DMF (3.3mL/mM peptide) followed by addition to 30 volumes of 0.1 M ammoniumbicarbonate, pH 7.5. The S-alkylation reaction carried out in thismanner is complete in 30 min. The resultingS—(N-hexylsuccinimido)-modified peptide monomer is purified bypreparative reverse-phase HPLC, followed by lyophilization as a fluffy,white powder.

Bis-succinimidohexane peptide heterodimers (wherein one peptide is theantibody and the other peptide is a Formula I compound wherein asubstituent on A or B of Formula I comprises a peptidyl moiety), may beprepared according to the method of Cheronis et al., supra fromcysteine-substituted peptides. A mixture of one part bis-maleimidohexaneis made with two parts peptide monomer in DMF (3.3 mL/mM peptide)followed by addition to 0.1 ammonium bicarbonate, pH 7.5. The reactionmixture is stirred at room temperature and is usually completed within30 min. The resulting bis-succinimidohexane peptide dimer is purified bypreparative reverse-phase HPLC. After lyophilization the material is afluffy, white powder.

Covalently linked adducts of the Formula I-L-Ab may be prepared byutilizing homo-bifunctional linking reagents (wherein the two reactivemoieties are the same), such as, for example, disuccinimidyl tartrate,disuccinimidyl suberate, ethylene glycolbis-(succinimidyl succinate),1,5-difluoro-2,4-dinitrobenzene (“DFNB”),4,4′-diisothiocyano-2,2′-disulfonic acid stilbene (“DIDS”), andbis-maleimidohexane (“BMH”). The linking reaction occurs randomlybetween the Ab and a compound of Formula I having a peptidyl moiety aspart of at least on substituent on A or B of Formula I.

Alternatively, hetero-bifunctional linking reagents may be employed.Such agents include, for example,N-succinimidyl-3-(2-pyridyldithio)propionate (“SPDP”),sulfosuccinimidyl-2-(p-azidosalicylamido)ethyl-1-3′-dithiopropionate(“SASD”, Pierce Chemical Company, Rockford, Ill.),N-maleimidobenzoyl-N-hydroxy-succinimidyl ester (“MBS”),m-maleimidobenzoylsulfosuccinimide ester (“sulfo-MBS”),N-succinimidyl(4-iodoacetyl)aminobenzoate (“SIAB”), succinimidyl4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (“SMCC”),succinimidyl-4-(p-maleimidophenyl)butyrate (“SMPB”),sulfosuccinimidyl(4-iodoacetyl)amino-benzoate (“sulfo-SIAB”),sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate(“sulfo-SMCC”), sulfosuccinimidyl 4-(p-maleimidophenyl)-butyrate(“sulfo-SMPB”), bromoacetyl-p-aminobenzoyl-N-hydroxy-succinimidyl ester,iodoacetyl-N-hydroxysuccinimidyl ester, and the like.

For hetero-bifunctional linking, a compound of Formula I is derivatizedwith, for example, the N-hydroxysuccinimidyl portion of the bifunctionalreagent, and the resulting derivatized compound is purified bychromatography. Next, a suitable tumor-specific Mab is reacted with thesecond functional group of the bifunctional linking reagent, assuring adirected sequence of binding between components of the desired adduct

Typical hetero-bifunctional linking agents for forming protein-proteinconjugates have an amino-reactive N-hydroxysuccinimide ester (NHS-ester)as one functional group and a sulfhydryl reactive group as the otherfunctional group. First, epsilon-amino groups of surface lysine residuesof either the Mab or the Formula I compound are acylated with theNHS-ester group of the cross-linking agent. The remaining component,possessing free sulfhydryl groups, is reacted with the sulfhydrylreactive group of the cross-linking agent to form a covalentlycross-linked dimer. Common thiol reactive groups include for example,maleimides, pyridyl disulfides, and active halogens. For example, MBScontains a NHS-ester as the amino reactive group, and a maleimide moietyas the sulfhydryl reactive group.

Photoactive hetero-bifunctional linking reagents, e.g., photoreactivephenyl azides, may also be employed. One such reagent, SASD, may belinked to either a Mab or to a Formula I compound wherein at least onesubstituent on A or B comprises a peptidyl moiety, via its NHS-estergroup. The conjugation reaction is carried out at pH 7 at roomtemperature for about 10 minutes. Molar ratios between about 1 and about20 of the cross-linking agent to the compounds to be linked may be used.

Numerous bifunctional linkers, useful as linkers (-L-), exist which havebeen used specifically for coupling small molecules to monoclonalantibodies, and many of these are commercially available. Examplesinclude N-succinimidyl-3-(2-pyridyldithio)-propionate (SPDP),2-iminothiolane (2-IT), 3-(4-carboxamidophenyldithio)propionthioimidate(CDPT), N-succinimidyl-acetylthioacetate (SATA),ethyl-S-acetyl-propionthioimidate (AMPT) andN-succinimidyl-3-(4-carboxamidophenyldithio)propionate (SCDP).Procedures for preparation of immunoconjugates using these linkers isdetailed in Toxin-Targeted Design for Anticancer Therapy. II:Preparation and Biological Comparison of Different Chemically LinkedGelonin-Antibody Conjugates (Cattel, et al, J. Pharm. Sci., 82:7, p699-704, 1993), (the entire disclosure of which is incorporated hereinby reference).

According to one embodiment of the invention the antibody comprises atumor-specific antibody, more preferably a tumor-specific monoclonalantibody or a tumor-specific monospecific polyclonal antibody.

Monoclonal antibodies may be advantageously cleaved by proteolyticenzymes to generate fragments retaining the antigen-binding site. Forexample, proteolytic treatment of IgG antibodies with papain at neutralpH generates two identical fragments, termed “Fab” fragments, eachcontaining one intact light chain disulfide-bonded to a fragment of theheavy chain (Fd). Each Fab fragment contains one antigen-combining site.The remaining portion of the IgG molecule is a dimer known as “Fc”.Similarly, pepsin cleavage at pH 4 results in the fragment, termed aF(ab′)2 fragment.

Methods for preparation of such fragments are known to those skilled inthe art. See, Goding, Monoclonal Antibodies Principles and Practice,Academic Press (1983), p. 119-123. Fragments of the anti-DBF-MAFmonoclonal antibodies containing the antigen binding site, such as Faband F(ab′)2 fragments, may be preferred in therapeutic applications,owing to their reduced immunogenicity. Such fragments are lessimmunogenic than the intact antibody, which contains the immunogenic Fcportion.

The effects of sensitization in the therapeutic use of animal originmonoclonal antibodies in the treatment of human disease may bediminished by employing a hybrid molecule generated from the same Fabfragment, but a different Fc fragment, than contained in Mab'spreviously administered to the same subject. It is contemplated thatsuch hybrid molecules formed from the monoclonal antibodies of theinvention may be used in therapy. The effects of sensitization arefurther diminished by preparing animal/human chimeric antibodies, e.g.,mouse/human chimeric antibodies, or humanized (i.e. CDR-grafted)antibodies. Such monoclonal antibodies comprise a variable region, i.e.,antigen binding region, and a constant region derived from differentspecies.

Chimeric animal-human monoclonal antibodies may be prepared byconventional recombinant DNA and gene transfection techniques well knownin the art. The variable region genes of a mouse antibody-producingmyeloma cell line of known antigen-binding specificity are joined withhuman immunoglobulin constant region genes. When such gene constructsare transfected into mouse myeloma cells, antibodies are produced whichare largely human but contain antigen-binding specificities generated inmice. As demonstrated by Morrison et al., Proc. Natl. Acad. Sci. USA 81,6851-6855, 30 1984, both chimeric heavy chain V region exon (VH)-humanheavy chain C region genes and chimeric mouse light chain V region exon(V*)-human * light chain gene constructs may be expressed whentransfected into mouse myeloma cell lines. When both chimeric heavy andlight chain genes are transfected into the same myeloma cell, an intactH₂L₂ chimeric antibody is produced. The methodology for producing suchchimeric antibodies by combining genomic clones of V and C region genesis described in the above-mentioned paper of Morrison et al., and byBoulianne et al., Nature 312, 642-646, 1984. Also see Tan et al., J.Immunol. 135, 3564-3567, 1985 for a description of high level expressionfrom a human heavy chain promotor of a human-mouse chimeric * chainafter transfection of mouse myeloma cells. As an alternative tocombining genomic DNA, cDNA clones of the relevant V and C regions maybe combined for production of chimeric antibodies, as described byWhitte et al., Protein Eng. 1, 499-505, 1987 and Liu et al., Proc. Natl.Acad. Sci. USA 84, 3439-3443, 1987.

For examples of the preparation of chimeric antibodies, see thefollowing U.S. Pat. Nos. 5,292,867; 5,091,313; 5,204,244; 5,202,238; and5,169,939. The entire disclosures of these patents, and the publicationsmentioned in the preceding paragraph, are incorporated herein byreference. Any of these recombinant techniques are available forproduction of rodent/human chimeric anti-DBP-MAF monoclonal antibodies.

To further reduce the immunogenicity of murine antibodies, “humanized”antibodies have been constructed in which only the minimum necessaryparts of the mouse antibody, the complementarity-determining regions(CDRs), are combined with human V region frameworks and human C regions(Jones et al., Nature 321, 522-525, 1986; Verhoeyen et al., Science 239,1534-1536, 1988; Reichmann et al., 322, 323-327, 1988; Hale et al.,Lancet 2, 1394-1399, 1988; Queen et al., Proc. Natl. Acad. Sci. USA 86,10029-10033, 1989). The entire disclosures of the aforementioned papersare incorporated herein by reference. This technique results in thereduction of the xenogeneic elements in the humanized antibody to aminimum. Rodent antigen binding sites are built directly into humanantibodies by transplanting only the antigen binding site, rather thanthe entire variable domain, from a rodent antibody. This technique isavailable for production of chimeric rodent/human antibodies of reducedhuman immunogenicity. Several such monoclonal antibodies, chimericanimal-human monoclonal antibodies, humanized antibodies andantigen-binding fragments thereof have been made available. Someexamples include:

Satumomab Pendetide (by Cytogen, a murine Mab directed against TAG-72);Igovomab (by CIS Bio, a murine Mab fragment Fab2 directed againsttumor-associated antigen CA 125); Arcitumomab (by Immunomedics, a murineMab fragment Fab directed against human carcinoembryonic antigen CEA);Capromab Pentetate (by Cytogen, a murine Mab directed against tumorsurface antigen PSMA); Tecnemab KI (by Sorin, murine Mab fragments(Fab/Fab2 mix) directed against HMW-MAA); Nofetumomab (by BoehringerIngelheim/NeoRx, murine Mab fragments (Fab) directed againstcarcinoma-associated antigen); Rituximab (by Genentech/IDECPharmaceuticals, a chimeric Mab directed against CD20 antigen on thesurface of B lymphocytes); Trastuzumab (by Genintech, a humanizedantibody directed against human epidermal growth factor receptor 2 (HER2)); Votumumab (by Organon Teknika, a human Mab directed againstcytokeratin tumor-associated antigen); Ontak (by Seragen/LigandPharmaceuticals, an IL-2-diphtheria toxin fusion protein that targetscells displaying a surface IL-2 receptor); IMC-C225 (by Imclone, achimerized monoclonal antibody that binds to EGFR); LCG-Mab (byCytoclonal Pharmaceutics Monoclonal antibody directed against lungcancer gene LCG) ABX-EGF (by Abgenix, a fully human monoclonal antibodyagainst the epidermal growth factor receptor (EGFr)); and Epratuzumab(by Immunomedics, a humanized, anti-CD22 monoclonal antibody).

Hence, compounds of Formula I can readily be covalently bonded toantibodies, preferably tumor-specific monoclonal antibodies (Nab) via asuitable bifunctional linker (-L-) to yield a conjugate of generalFormula, I-L-Ab. In addition, compounds of Formulae Ie, Iz and IA can becovalently bonded to antibodies (Ab), preferably tumor-specificmonoclonal antibodies (Mab) via a suitable bifunctional linker (-L-) toyield conjugates of general Formula, Ie-L-Ab, Iz-L-Ab or IA-L-Ab. Ageneral synthetic route for preparing compounds of the present inventionof general Formula I-L-Ab is shown in Scheme 13, wherein: {circle around(I)}—NH₂ is a compound according to Formula I wherein at least onesubstituent on the A or B ring is —NH₂.

GEOMETRIC AND STEREO ISOMERISM IN COMPOUNDS OF THE INVENTION

E-/Z-Isomerism

The α,β-unsaturated sulfoxides of the invention are characterized byisomerism resulting from the presence of an olefinic double bond. Thisisomerism is commonly referred to as cis-trans isomerism, but the morecomprehensive naming convention employs E- and Z-designations. Thecompounds are named according to the Cahn-Ingold-Prelog system, theIUPAC 1974 Recommendations, Section E: Stereochemistry, in Nomenclatureof Organic Chemistry, John Wiley & Sons, Inc., New York, N.Y., 4^(th)ed., 1992, p. 127-138, the entire contents of which is incorporatedherein by reference. Using this system of nomenclature, the four groupsabout a double bond are prioritized according to a series of rules.Then, that isomer with the two higher ranking groups on the same side ofthe double bond is designated Z (for the German word “zusammen”, meaningtogether). The other isomer, in which the two higher-ranking groups areon opposite sides of the double bond, is designated E (for the Germanword “entgegen”, which means “opposite”). Thus if the four groups on acarbon-carbon double bond are ranked, A being the lowest rank and Dbeing highest, A>B>C>D, the isomers would be named as in Scheme 14.

Unless otherwise indicated, both configurations, as depicted below inScheme 15, and mixtures thereof, are included in the scope of“α,β-unsaturated sulfoxides.”

B. Optical Isomerism

The present invention is also directed to isolated optical isomers ofcompounds according to Formula I. The isomers resulting from thepresence of a chiral center comprise a pair of nonsuperimposable isomersthat are called “enantiomers.” Single enantiomers of a pure compound areoptically active, i.e., they are capable of rotating the plane of planepolarized light. Single enantiomers are designated according to theCahn-Ingold-Prelog system. See March, Advanced Organic Chemistry, 4^(th)Ed., (1992), p. 109. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated (R) and ifthe descending rank of the other groups proceeds counterclockwise, themolecule is designated (S). In the example in Scheme 16, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer.

Sulfoxides of Formula I have at least one chiral center which is thesulfoxide sulfur atom. In addition compounds of Formula I wherein n is Iand R¹ is other than hydrogen potentially have a second chiral center.

For the sulfoxide chiral center in compounds of the present invention,the lowest priority (an empty orbital) and the highest priority (thesulfoxide oxygen) atoms about the chiral sulfur are fixed. Thus, theabsolute configuration of compounds of the invention depends on thepriority ranking of the two carbon atoms bonded to the sulfoxide groupas shown in Scheme 17.

Certain compounds may have more than one chiral center, e.g., n is I andR¹ is other than —H. If a compound has more than one chiral center,diastereomeric isomerism results, as exemplified in Scheme 18.

The present invention is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization.

By “isolated optical isomer” means a compound which has beensubstantially purified from the corresponding optical isomer(s) of thesame formula. Preferably, the isolated isomer is at least about 80%,more preferably at least 90% pure, even more preferably at least 98%pure, most preferably at least about 99% pure, by weight.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound having the structure of Formula I, or achiral intermediate thereof, is separated into 99% wt.% pure opticalisomers by HPLC using a suitable chiral column, such as a member of theseries of DAICEL CHIRALPAK family of columns (Daicel ChemicalIndustries, Ltd., Tokyo, Japan). The column is operated according to themanufacturer's instructions.

SALTS OF COMPOUNDS OF THE INVENTION

The compounds of the present invention may take the form of salts. Theterm “salts”, embraces salts commonly used to form alkali metal saltsand to form addition salts of free acids or free bases. The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range so as to have utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility in asynthetic process. Suitable pharmaceutically-acceptable acid additionsalts may be prepared from an inorganic acid or from an organic acid.Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, beta-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include for example, metallic salts made from calcium,magnesium, potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable salts include lithium salts and cyanatesalts. All of these salts may be prepared by conventional means from thecorresponding α,β-unsaturated sulfoxide by reacting, for example, theappropriate acid or base with the compound of Formula I.

Pharmaceutical Compositions

The sulfoxides of the invention may be administered in the form of apharmaceutical composition, in combination with a pharmaceuticallyacceptable carrier. The active ingredient in such formulations maycomprise from 0.1 to 99.99 weight percent. By “pharmaceuticallyacceptable carrier” is meant any carrier, diluent or excipient which iscompatible with the other ingredients of the formulation and notdeleterious to the recipient.

The compounds of the invention may be administered to individuals(mammals, including animals and humans) afflicted with cancer.

The compounds are also useful in the treatment of non-cancerproliferative disorders, that is, proliferative disorders which arecharacterized by benign indications. Such disorders may also be known as“cytoproliferative” or “hyperproliferative” in that cells are made bythe body at an atypically elevated rate. Such disorders include, but arenot limited to, the following: hemangiomatosis in new born, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

ADMINISTRATION OF COMPOUNDS OF THE INVENTION

The compounds may be administered by any route, including oral andparenteral administration. Parenteral administration includes, forexample, intravenous, intramuscular, intraarterial, intraperitoneal,intranasal, rectal, intravaginal, intravesical (e.g., to the bladder),intradermal, topical or subcutaneous administration. Also contemplatedwithin the scope of the invention is the instillation of drug in thebody of the patient in a controlled formulation, with systemic or localrelease of the drug to occur at a later time. For example, the drug maylocalized in a depot for controlled release to the circulation, or forrelease to a local site of tumor growth.

The active agent is preferably administered with a pharmaceuticallyacceptable carrier selected on the basis of the selected route ofadministration and standard pharmaceutical practice. The active agentmay be formulated into dosage forms according to standard practices inthe field of pharmaceutical preparations. See Alphonso Gennaro, ed.,Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack PublishingCo., Easton, Pa. Suitable dosage forms may comprise, for example,tablets, capsules, solutions, parenteral solutions, troches,suppositories, or suspensions.

For parenteral administration, the active agent may be mixed with asuitable carrier or diluent such as water, an oil (particularly avegetable oil), ethanol, saline solution, aqueous dextrose (glucose) andrelated sugar solutions, glycerol, or a glycol such as propylene glycolor polyethylene glycol. Solutions for parenteral administrationpreferably contain a water soluble salt of the active agent. Stabilizingagents, antioxidizing agents and preservatives may also be added.Suitable antioxidizing agents include sulfite, ascorbic acid, citricacid and its salts, and sodium EDTA. Suitable preservatives includebenzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol. Thecomposition for parenteral administration may take the form of anaqueous or nonaqueous solution, dispersion, suspension or emulsion.

For oral administration, the active agent may be combined with one ormore solid inactive ingredients for the preparation of tablets,capsules, pills, powders, granules or other suitable oral dosage forms.For example, the active agent may be combined with at least oneexcipient such as fillers, binders, humectants, disintegrating agents,solution retarders, absorption accelerators, wetting agents absorbentsor lubricating agents. According to one tablet embodiment, the activeagent may be combined with carboxymethylcellulose calcium, magnesiumstearate, mannitol and starch, and then formed into tablets byconventional tableting methods.

The specific dose of a compound according to the invention to obtaintherapeutic benefit for treatment of a proliferative disorder will, ofcourse, be determined by the particular circumstances of the individualpatient including, the size, weight, age and sex of the patient, thenature and stage of the proliferative disorder, the aggressiveness ofthe proliferative disorder, and the route of administration of thecompound.

For example, a daily dosage of from about 0.05 to about 50 mg/kg/day maybe utilized. Higher or lower doses are also contemplated.

Radioprotection

The compounds of the invention are further believed useful in theprotection of normal cells from the cytotoxic and genetic effects ofexposure to radiation, in individuals who have incurred, who will in thefuture incur and who are at risk for incurring exposure to ionizingradiation.

The specific dose of compound according to the invention to obtaintherapeutic benefit for radioprotection will, be determined by theparticular circumstances of the individual patient including, the size,weight, age and sex of the patient, the type, dose and timing of theionizing radiation, and the route of administration of the compound ofthe invention.

For example, a daily dosage of from about 0.05 to about 50 mg/kg/day maybe utilized. Higher or lower doses are also contemplated.

Exposure to radiation by an individual may comprise therapeuticradiation administered to the individual or in some indications, to bonemarrow removed from the individual.

An individual may also be exposed to ionizing radiation fromoccupational or environmental sources, as discussed in the backgroundsection.

For purposes of the invention, the source of the radiation is not asimportant as the type (Le., acute or chronic) and dose level absorbed bythe individual. It is understood that the following discussionencompasses ionizing radiation exposures from both occupational andenvironmental sources.

Individuals suffering from effects of acute or chronic exposure toionizing radiation that are not immediately fatal are said to haveremediable radiation damage. Such remediable radiation damage can bereduced or eliminated by the compounds and methods of the presentinvention.

An acute dose of ionizing radiation which may cause remediable radiationdamage includes a localized or whole body dose, for example, betweenabout 10,000 millirem (0.1 Gy) and about 1,000,000 millirem (10 Gy) in24 hours or less, preferably between about 25,000 millirem (0.25 Gy) andabout 200,000 (2 Gy) in 24 hours or less, and more preferably betweenabout 100,000 millirem (1 Gy) and about 150,000 millirem (1.5 Gy) in 24hours or less.

A chronic dose of ionizing radiation which may cause remediableradiation damage includes a whole body dose of about 100 millirem (0.001Gy) to about 10,000 millirem (0.1 Gy), preferably a dose between about1000 millirem (0.01 Gy) and about 5000 millirem (0.05 Gy) over a periodgreater than 24 hours, or a localized dose of 15,000 millirem (0.15 Gy)to 50,000 millirem (0.5 Gy) over a period greater than 24 hours.

Radioprotection: Therapeutic Ionizing Radiation

For radioprotective administration to individuals receiving therapeuticionizing radiation, the compounds of the invention should beadministered far enough in advance of the therapeutic radiation suchthat the compound is able to reach the normal cells of the individual insufficient concentration to exert a radioprotective effect on the normalcells. The pharmacokinetics of specific compounds may be determined bymeans known in the art and tissue levels of a compound in a particularindividual may be determined by conventional analyses.

The compound may be administered as much as about 24 hours, preferablyno more than about 18 hours, prior to administration of the radiation.In one embodiment, the therapy is administered at least about 3-12 hoursbefore administration of the therapeutic radiation. Most preferably, thecompound is administered once at about 18 hours and again at about 6hours before the radiation exposure.

One or more α,β-unsaturated sulfoxides may be administeredsimultaneously, or different α,β-unsaturated sulfoxides may beadministered at different times during the treatment.

Where the therapeutic radiation is administered in serial fashion, it ispreferable to intercalate the administration of one or moreradioprotective compounds within the schedule of radiation treatments.As above, different radioprotective compounds of the invention may beadministered either simultaneously or at different times during thetreatment. Preferably, an about 24-hour period separates administrationof the radioprotective compound and the therapeutic radiation. Morepreferably, the administration of the radioprotective compound and thetherapeutic radiation is separated by about 6 to 18 hours. This strategywill yield significant reduction of radiation-induced side effectswithout affecting the anticancer activity of the therapeutic radiation.

For example, therapeutic radiation at a dose of 0.1 Gy may be givendaily for five consecutive days, with a two-day rest, for a total periodof 6-8 weeks. One or more α,β-unsaturated sulfoxides may be administeredto the individual 18 hours previous to each round of radiation. Itshould be pointed out, however, that more aggressive treatmentschedules, i.e., delivery of a higher dosage, is contemplated accordingto the present invention due to the protection of the normal cellsafforded by the radioprotective compounds. Thus, the radioprotectiveeffect of the compound increases the therapeutic index of thetherapeutic radiation, and may permit the physician to safely increasethe dosage of therapeutic radiation above presently recommended levelswithout risking increased damage to the surrounding normal cells andtissues.

Radioprotection: Radiation-Treated Bone Marrow

The radioprotective compounds of the invention are further useful inprotecting normal bone marrow cells from radiologic treatments designedto destroy hematologic neoplastic cells or tumor cells which havemetastasized into the bone marrow. Such cells include, for example,myeloid leukemia cells. The appearance of these cells in the bone marrowand elsewhere in the body is associated with various disease conditions,such as the French-American-British (FAB) subtypes of acute myelogenousleukemias (AML), chronic myeloid leukemia (CML), and acute lymphocyticleukemia (ALL).

CML, in particular, is characterized by abnormal proliferation ofimmature granulocytes (e.g., neutrophils, eosinophils, and basophils) inthe blood, bone marrow, spleen, liver, and other tissues andaccumulation of granulocytic precursors in these tissues. The individualwho presents with such symptoms will typically have more than 20,000white blood cells per microliter of blood, and the count may exceed400,000. Virtually all CML patients will develop “blast crisis”, theterminal stage of the disease during which immature blast cells rapidlyproliferate, leading to death.

Other individuals suffer from metastatic tumors, and require treatmentwith total body irradiation (TBI). Because TBI will also kill theindividual's hematopoietic cells, a portion of the individual's bonemarrow is removed prior to irradiation for subsequent reimplantation.However, metastatic tumor cells are likely present in the bone marrow,and reimplantation often results in a relapse of the cancer within ashort time.

Individuals presenting with neoplastic diseases of the bone marrow ormetastatic tumors may be treated by removing a portion of the bonemarrow (also called “harvesting”), purging the harvested bone marrow ofmalignant stem cells, and reimplanting the purged bone marrow.Preferably, the individual is treated with radiation or some otheranti-cancer therapy before the autologous purged bone marrow isreimplanted.

Thus, the invention provides a method of reducing the number ofmalignant cells in bone marrow, comprising the steps of removing aportion of the individual's bone marrow, administering an effectiveamount of at least one radioprotective compound according to the presentinvention and irradiating the treated bone marrow with a sufficient doseof ionizing radiation such that malignant cells in the bone marrow arekilled. As used herein, “malignant cell” means any uncontrollablyproliferating cell, such a tumor cell or neoplastic cell. Theradioprotective compounds protect the normal hematopoietic cells presentin the bone marrow from the deleterious effects of the ionizingradiation. The compounds also exhibit a direct killing effect on themalignant cells. The number of malignant cells in the bone marrow issignificantly reduced prior to reimplantation, thus minimizing theoccurrence of a relapse.

Preferably, each α,β-unsaturated sulfoxide is administered to the bonemarrow in a concentration from about 0.25 to about 100 micromolar; morepreferably, from about 1.0 to about 50 micromolar; in particular fromabout 2.0 to about 25 micromolar. Particularly preferred concentrationsare 0.5, 1.0 and 2.5 micromolar and 5, 10 and 20 micromolar. Higher orlower concentrations may also be used.

The radioprotective compounds may be added directly to the harvestedbone marrow, but are preferably dissolved in an organic solvent such asdimethylsulfoxide (DMSO). Pharmaceutical compositions of α,β-unsaturatedsulfoxides such as are described in more detail below may also be used.

Preferably, the radioprotective compound is added to the harvested bonemarrow about 20 hours prior to radiation exposure, preferably no morethan about 24 hours prior to radiation exposure. In one embodiment, theradioprotective compound is administered to the harvested bone marrow atleast about 6 hours before radiation exposure. One or more compounds maybe administered simultaneously, or different compounds may beadministered at different times. Other dosage regimens are alsocontemplated.

If the individual is to be treated with ionizing radiation prior toreimplantation of the purged bone marrow, the individual may be treatedwith one or more radioprotective compounds prior to receiving theionizing radiation dose, as described above.

Radioprotection: Environmental or Occupational Radiation Exposure

The invention also provides a method for treating individuals who haveincurred remediable radiation damage from acute or chronic exposure toionizing radiation, comprising reducing or eliminating the cytotoxiceffects of radiation exposure on normal cells and tissues byadministering an effective amount of at least one radioprotectivecompound. The compound is preferably administered in as short a time aspossible following radiation exposure, for example between 0-6 hoursfollowing exposure.

Remediable radiation damage may take the form of cytotoxic and genotoxic(i.e., adverse genetic) effects in the individual. In anotherembodiment, there is therefore provided a method of reducing oreliminating the cytotoxic and genotoxic effects of radiation exposure onnormal cells and tissues, comprising administering an effective amountof at least one radioprotective compound prior to acute or chronicradiation exposure. The compound may be administered, for example about24 hours prior to radiation exposure, preferably no more than about 18hours prior to radiation exposure. In one embodiment, the compound isadministered at least about 6 hours before radiation exposure. Mostpreferably, the compound is administered at about 18 and again at about6 hours before the radiation exposure. One or more radioprotectivecompounds may be administered simultaneously, or differentradioprotective compounds may be administered at different times.

When multiple acute exposures are anticipated, the radioprotectivecompounds of the invention may be administered multiple times. Forexample, if fire or rescue personnel must enter contaminated areasmultiple times, radioprotective compounds of the invention may beadministered prior to each exposure. Preferably, an about 24-hour periodseparates administration of the compound and the radiation exposure.More preferably, the administration of radioprotective compounds and theradiation exposure is separated by about 6 to 18 hours. It is alsocontemplated that a worker in a nuclear power plant may be administeredan effective amount of a radioprotective compound of the invention priorto beginning each shift, to reduce or eliminate the effects of exposureto ionizing radiation.

If an individual is anticipating chronic exposure to ionizing radiation,the radioprotective compound may be administered periodically throughoutthe duration of anticipated exposure. For example, a nuclear power plantworker or a soldier operating in a forward area contaminated withradioactive fallout may be given the radioprotective compound every 24hours, preferably every 6-18 hours, in order to mitigate the effects ofradiation damage. Likewise, the radioprotective compound may beperiodically administered to civilians living in areas contaminated byradioactive fallout until the area is decontaminated or the civiliansare removed to a safer environment.

Chemoprotection

The compounds of the invention are believed useful in protectingindividuals from the cytotoxic side effects of chemotherapeutic agents,particularly mitotic phase cell cycle inhibitors and topoisomeraseinhibitors, used in the treatment of cancer and other proliferativedisorders.

The specific dose of a compound according to the invention to obtaintherapeutic benefit for chemoprotection will be determined by theparticular circumstances of the individual patient including, the size,weight, age and sex of the patient, the type and dose of theadministered chemotherapy, the nature and stage and cell damage, and theroute of administration of the compound of the invention.

For example, a daily dosage of from about 0.05 to about 50 mg/kg/day maybe utilized. Higher or lower doses are also contemplated.

For providing cytoprotection from cytotoxic effects of chemotherapeuticagents, the schedule of administration of the cytotoxic drug, i.e.,mitotic phase cell cycle inhibitor or topoisomerase inhibitor, can beany schedule with the stipulation that the α,β-unsaturated sulfoxide isadministered prior to the cytotoxic drug. The cytoprotective compoundshould be administered far enough in advance of the cytotoxic drug suchthat the former is able to reach the normal cells of the patient insufficient concentration to exert a cytoprotective effect on the normalcells. Again, individual drug pharmacokinetics and blood levels of aspecific drug in a specific patient are factors that may be determinedby methods known in the art.

The cytoprotective compound is administered at least about 1 hour,preferably, at least about 2 hours, and more preferably, at least about4 hours, before administration of the cytotoxic drug. The compound maybe administered as much as about 48 hours, preferably no more than about36 hours, prior to administration of the cytotoxic drug. Mostpreferably, the compound is administered about 24 hours before thecytotoxic drug. The compound may be administered more or less than 24hours before the cytotoxic effect, but the protective effect of thecompounds is greatest when administered about 24 hours before thecytotoxic drug. One or more cytotoxic drugs may be administered.Similarly, one or more of the α,β-unsaturated sulfoxides may becombined.

Where the cytotoxic drug or drugs is administered in serial fashion, itmay prove practical to intercalate cytoprotective compounds of theinvention within the schedule with the caveat that a 448 hour period,preferably a 12-36 hour period, most preferably a 24 hour period,separates administration of the two drug types. This strategy will yieldpartial to complete eradication of cytotoxic drug side effects withoutaffecting anticancer activity.

For example, the mitotic inhibitor may be given daily, or every fourthday, or every twenty-first day. The α,β-unsaturated sulfoxide may begiven 24 hours previous to each round of inhibitor administration, bothas a cytoprotective agent and as an antitumor agent.

The practice of the invention is illustrated by the followingnon-limiting examples. In each of the following examples, the sulfinylacetic acid compound A-CH₂—SO—CH₂—COOH is made according to Part A ofGeneral Procedure 1: Synthesis of (E)-α,β Unsaturated Sulfoxides, above.The (Z)-sulfide intermediates are made according to Part A of GeneralProcedure 2: Synthesis of (Z)-α,β Unsaturated Sulfoxides, above. Thefinal (E)- and (Z)-sulfoxide compounds A-(CHR¹)_(n)—SO—CH═CH—B arerecrystallized from 2-propanol and the purity is ascertained by HPLC.

EXAMPLES 1-14 Synthesis of (E) Compounds of the Invention

A solution of a sulfinyl acetic acid X (10 mmol) and a carboxaldehyde Y(10 mmol) from Table 4 is subjected to General Procedure 1, Step C. Theresulting product is purified by column chromatography on silica gel toyield the reaction product listed in Table 4. TABLE 4 Sulfinyl aceticEx. # acid X carboxaldehyde Y Reaction Product 1 4-fluorobenzyl-2-pyridine- (1E)-1-{[(4-fluorophenyl)- sulfinylacetic acidcarboxaldehyde methyl]sulfinyl}-2-(2-pyridyl)-ethene 2 4-fluorobenzyl-3-pyridine- (1E)-1-{[(4-fluorophenyl)- sulfinylacetic acidcarboxaldehyde methyl]sulfinyl}-2-(3-pyridyl)- ethene 3 4-fluorobenzyl-4-pyridine- (1E)-1-{[(4-fluorophenyl)- sulfinylacetic acidcarboxaldehyde methyl]sulfinyl}-2-(4-pyridyl)- ethene 4 4-chlorobenzyl-2-pyridine- (1E)-1-{[(4-chlorophenyl)- sulfinylacetic acidcarboxaldehyde methyl]sulfinyl}-2-(2-pyridyl)- ethene 5 4-chlorobenzyl-3-pyridine- (1E)-1-{[(4-chlorophenyl)- sulfinylacetic acidcarboxaldehyde methyl]sulfinyl}-2-(3-pyridyl)- ethene 6 4-chlorobenzyl-4-pyridine- (1E)-1-{[(4-chlorophenyl)- sulfinylacetic acidcarboxaldehyde methyl]sulfinyl}-2-(4-pyridyl)- ethene 7 4-bromobenzyl-2-pyridine- (1E)-1-{[(4-bromophenyl)- sulfinylacetic acid carboxaldehydemethyl]sulfinyl}-2-(2-pyridyl)- ethene 8 4-bromobenzyl- 3-pyridine-(1E)-1-{[(4-bromophenyl)- sulfinylacetic acid carboxaldehydemethyl]sulfinyl}-2-(3-pyridyl)- ethene 9 4-bromobenzyl- 4-pyridine-(1E)-1-{[(4-bromophenyl)- sulfinylacetic acid carboxaldehydemethyl]sulfinyl}-2-(4-pyridyl)- ethene 10 4-fluorobenzyl- 2-thiophene-(1E)-1-{[(4-fluorophenyl)- sulfinylacetic acid carboxaldehydemethyl]sulfinyl}-2-(2-thienyl)- ethene 11 4-chlorobenzyl- 2-thiophene-(1E)-1-{[(4-chlorophenyl)- sulfinylacetic acid carboxaldehydemethyl]sulfinyl}-2-(2-thienyl)- ethene 12 4-bromobenzyl- 2-thiophene-(1E)-1-{[(4-bromophenyl)- sulfinylacetic acid carboxaldehydemethyl]sulfinyl}-2-(2-thienyl)- ethene 13 4-fluorobenzyl-4-bromo-2-thiophene- (1E)-2-(4-bromo(2-thienyl))-1- sulfinylacetic acidcarboxaldehyde {[(4-fluorophenyl)methyl]- sulfinyl}ethene; 144-chlorobenzyl- 4-bromo-2-thiophene- (1E)-2-(4-bromo(2-thienyl))-1-sulfinylacetic acid carboxaldehyde {[(4-chlorophenyl)methyl]-sulfinyl}ethene;

EXAMPLES 15-28 Synthesis of (Z)-Compounds of the Invention

A solution of an aryl or heteroaryl acetylene A and a mercaptan B(provided in Table 5) are subjected to General Procedure 2, Step A, toform sulfide C. Sulfide C is then oxidized according to GeneralProcedure 2, step B, to yield sulfoxide D, which is purified by columnchromatography and/or cyrstallization. TABLE 5 Ex. # acetylene Amercaptan B sulfide C sulfoxide D 15 4-chlorophenyl- 4-chlorobenzyl(1Z)-2-(4-chlorophenyl)- (1Z)-2-(4-chlorophenyl)-1- acetylene mercaptan1-[(4-chloro-phenyl)- {[(4-chlorophenyl)- methylthio]ethenemethyl]sulfinyl}ethene 16 4-chlorophenyl- 2-chlorobenzyl(1Z)-2-(4-chlorophenyl)- (1Z)-2-(4-chloro-phenyl)- acetylene mercaptan1-[(2-chloro-phenyl)- 1-{[(2-chlorophenyl)- methylthio]ethenemethyl]sulfinyl}ethene 17 4-chlorophenyl- 4-fluorobenzyl(1Z)-2-(4-chlorophenyl)- (1Z)-2-(4-chlorophenyl)-1- acetylene mercaptan1-[(2-fluoro-phenyl)- {[(2-fluorophenyl)- methylthio]ethenemethyl]sulfinyl}ethene 18 4-fluorophenyl- benzyl(1Z)-2-(4-fluorophenyl)- (1Z)-2-(4-fluorophenyl)-1- acetylene mercaptan1-(benzyllthio)ethene [benzylsulfinyl]ethene 19 4-fluorophenyl-4-chlorobenzyl (1Z)-2-(4-fluorophenyl)- (1Z)-2-(4-fluorophenyl)-1-acetylene mercaptan 1-[(4-chloro-phenyl)- {[(4-chlorophenyl)-methylthio]ethene methyl]sulfinyl}ethene 20 4-fluorophenyl-2-chlorobenzyl (1Z)-2-(4-fluorophenyl)- (1Z)-2-(4-fluorophenyl)-1-acetylene mercaptan 1-[(2-chloro-phenyl-) {[(2-chlorophenyl)-methylthio]ethene methyl]sulfinyl}ethene 21 4-fluorophenyl-4-fluorobenzyl (1Z)-2-(4-fluorophenyl)- (1Z)-2-(4-fluorophenyl)-1-acetylene mercaptan 1-[(4-fluoro-phenyl)- {[(2-fluorophenyl)-methylthio]ethene methyl]sulfinyl}ethene 22 4-bromophenyl- benzyl(1Z)-2-(4-bromophenyl)- (1Z)-2-(4-bromophenyl)-1- acetylene mercaptan1-(benzyllthio)- [benzylsulfinyl]ethene ethene 23 4-bromophenyl-4-chlorobenzyl (1Z)-2-(4-bromophenyl)- (1Z)-2-(4-bromophenyl)-1-acetylene mercaptan 1-[(4-chlorophenyl)- {[(4-chloro-phenyl)-methylthio]ethene methyl]sulfinyl}-ethene 24 4-bromophenyl-2-chlorobenzyl (1Z)-2-(4-bromophenyl)- (1Z)-2-(4-bromophenyl)-1-acetylene mercaptan 1-[(2-chloro-phenyl)- {[(2-chlorophenyl)-methylthio]ethene methyl]sulfinyl}-ethene 25 4-bromophenyl-4-fluorobenzyl (1Z)-2-(4-bromophenyl)- (1Z)-2-(4-bromophenyl)-1-acetylene mercaptan 1-[(4-fluoro-phenyl)- {[(4-fluorophenyl)-methylthio]ethene methyl]sulfinyl}-ethene 26 4-methylphenyl- benzyl(1Z)-2-(4-methylphenyl)- (1Z)-2-(4-methylphenyl)-1- acetylene mercaptan1-(benzyllthio)- [benzylsulfinyl]ethene ethene 27 4-methylphenyl-4-chlorobenzyl (1Z)-2-(4-methylphenyl)- (1Z)-2-(4-methylphenyl)-1-acetylene mercaptan 1-[(4-chloro-phenyl)- {[(4-chloro-phenyl)-methylthio]ethene methyl]sulfinyl}-ethene 28 4-methylphenyl-2-chlorobenzyl (1Z)-2-(4-methylphenyl)- (1Z)-2-(4-methylphenyl)-1-acetylene mercaptan 1-[(2-chloro-phenyl)- {[(2-chloro-phenyl)-methylthio]ethene methyl]sulfinyl}-ethene

EXAMPLES 29-32 Preparation of Additional (E)-Compounds of the Invention

Further (E)-compounds of the invention are prepared according to Scheme19. Compounds prepared according to Scheme 19 are listed in Table 6below.

Step A. General Preparation of Benzylthioacetic acids 11a-d.

To a cold (about 0° C.) solution of sodium hydroxide (40 g, 1 mol) inmethanol (500 mL) was added thioglycollic acid (46 g, 0.5 mol) slowlyover 30 minutes. A solid precipitate of sodium thioglycollate formed.The precipitate was dissolved by stirring and warming the mixture toabout 50° C. After dissolution of the precipitated sodiumthioglycollate, the resulting solution was cooled to room temperature(25° C.). To the cooled solution was added the substituted benzylchloride (10a, 10b, 10c or 10d) (0.5 mol) portionwise at a rate whereinthe temperature of the resulting mixture was kept below 40° C. duringthe addition. When the addition of the substituted benzyl chloride wascomplete, the resulting mixture was warmed to reflux and maintained atreflux temperature for 2 hours. The hot mixture was then cooled to roomtemperature (25° C.) and poured onto crushed ice (1 Kg) containinghydrochloric acid (12M, 100 mL). A white precipitate formed. Theprecipitate was filtered, washed with ice cold water (3×100 mL) anddried under vacuum to yield the desired benzylthioacetic acid (11a, 11b,11c or 11d).

Step B. General Preparation of Benzylsulfinylacetic acids 12a-12d.

To a vigorously stirred solution of sodium hydroxide (3 g, 0.076 mol) indeionized water (150 mL) was added a substituted benzylthioacetic acid(11a, 11b, 11c or 11d) prepared according to Step A (0.058 mol). Theresulting suspension was stirred for 10 minutes at room temperature (25°C.). To the stirred solution was added sodium bicarbonate (39.25 g,0.467 mol) and acetone (49 mL). The resulting mixture was cooled toabout 1° C. To the cooled solution was added a solution of potassiumperoxymonosulfate (0.038 mol) dissolved in aqueousethylenediaminetetraacetic acid (EDTA) (123 mL of 0.004M solution) over10 min to form a reaction mixture as a suspension. The reactiontemperature was kept below 5° C. during the addition of the potassiumperoxymonosulfate solution. The reaction mixture was stirred for 5 min.The reaction was then quenched by the addition of aqueous sodiumbisulfite (14.7 g in 30 mL water) at 2° C. The quenched reaction mixturewas acidified by addition of aqueous HCl (6N, 88 mL). Sodium chloride(73.6 g) was added to the acidified reaction mixture and the resultingmixture was extracted with ethyl acetate (2×75 mL). The ethyl acetateextracts were combined and washed with deionized water (50 mL) and brine(50 mL), and then dried over anhydrous MgSO₄. The dried extract wasfiltered and concentrated under vacuum to yield the desired substitutedbenzyl sulfonylacetic acid compounds (yield 64-73%). Compound 12a:m.p=110-111° C. Compound 12b: m.p.=142-146° C. Compound 12c:m.p.=144-146 ° C. Compound 12d: m.p.=124-126° C.

Step C. General Preparation of Compounds of Examples 29-32.

To a solution of a substituted benzylsulfinylacetic acid (12a, 12b, 12cor 12d) prepared according to Step B (10 mmol) in toluene (100 mL, 25°C.) was added catalytic amounts of piperidine (0.1 mL) and benzoic acid(134 mg). To the resulting mixture was added a substituted benzaldehyde13a or 13b (10 mmol) to form a reaction mixture. The reaction mixturewas warmed to reflux temperature and maintained at reflux for 6 hours ina reaction vessel equipped with Dean-Stark trap. After 6 hours, thereaction mixture was cooled to room temperature (25° C.). The cooledreaction mixture was washed successively with saturated aqueous sodiumhydrogen carbonate (3×30 mL), saturated aqueous sodium bisulfite (1×40mL), aqueous hydrochloric acid (1N, 1×40 mL), and water (1×60 mL). Thetoluene layer was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to yield a solid residue. The solid residueobtained after concentration was purified by crystallization or bysilica gel column chromatography to yield the following desiredcompounds as listed in Table 6. TABLE 6 Ex- ample M.P. # Yield ° C.Structure 29 27% 92-94

30 33% 140-146

31 18% 112-115

32 43% 270-274

33 24 136-140

EXAMPLE 33 Preparation of(E)-2,4,6-trimethoxystyryl-4-methoxy-3-aminobenzylsulfoxide by Reductionof (E)-2,4,6-trimethoxystyryl-4-methoxy-3-nitrobenzylsulfoxide

(E)-2,4,6-Trimethoxystyryl-4-methoxy-3-nitrobenzylsulfoxide (1.3 mmol)was dissolved in a 2 to 1 mixture of acetone and water (50 mL). Theresulting mixture was heated to 50° C. After heating at 50° C. for 30min, sodium dithionite (26.3 mmol) was added to the heated reactionmixture (portionwise over 20 minutes). The resulting mixture wasmaintained at 50° C. for 1 hour, then cooled to room temperature (25°C.). Water (50 mL) was added to the cooled mixture. The resultingmixture was extracted with ethyl acetate (3×50 mL). The ethyl acetateextracts were combined and washed with saturated aqueous NaHCO₃. Theethyl acetate extract was dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to yield the crude product. Thecrude product was recrystallized from 2-propanol to afford the desired(E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfoxide, as listedin Table 6.

EXAMPLE 34 Oxidation of (E)-2,4,6-trimethoxystyryl-4-methoxybenzlSulfoxide (a Compound of the Invention) to prepare(E)-2,4,6-trimethoxystyryl-4-methoxybenzyl Sulfone

(E)-2,4,6-trimethoxystyryl-4-methoxybenzyl sulfoxide (3 g) is dissolvedin glacial acetic acid (30 mL) and cooled to 0° C. To the cooledsolution is added hydrogen peroxide (7.5 mL of a 30% solution) to form areaction mixture. The reaction mixture is heated to reflux temperatureand maintained at reflux for 1 hour. After 1 hour, the heated reactionmixture is poured onto crushed water ice (200 g). A solid precipitate isformed. The precipitate is separated by filtration, dried, andrecrystallized from 2-propanol to yield the desired(E)-2,4,6-trimethoxystyryl-4-methoxybenzyl sulfone.

EXAMPLE 35 Effect of α,β-Unsaturated Sulfoxides on Tumor Cell Lines

A. Cells.

B. Treatment with Sulfoxides and Viability Assay

The effect of the α,β-unsaturated sulfoxides according to Formula I ontumor cells of prostate, colon, lung and breast origin was examined byutilizing the following cell lines: prostate tumor cell line DU-145;colorectal carcinoma cell line DLD-1; non-small cell lung carcinoma cellline H157; and breast tumor cell line BT-20. BT-20 is anestrogen-unresponsive cell line. BT-20, DLD-1 and H157 were grown inDulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovineserum supplemented with penicillin and streptomycin. DU145 was culturedin RPMI with 10% fetal bovine serum containing penicillin andstreptomycin. NIH/3T3 (normal murine fibroblasts) and HFL-1 cells(normal diploid human lung fibroblasts) were grown in DMEM containing10% calf serum supplemented with penicillin and streptomycin.

Cells were plated at density levels of 1.0×10⁵ cells per well insix-well plates. Cell cultures were maintained at 37° C. in a humidifiedatmosphere of 5% CO₂.

Cells were treated with compounds of the invention at doses ranging from10 nM to 5 μM concentration, and cell viability was determined after 96hours by the Trypan blue exclusion method.

The results are set forth in Table 7. Values are reported as the GI₅₀,i.e., the concentration (μM) required for 50% growth inhibition ascompared to vehicle (DMSO) treated cells. The values reported in Table 7are: ***=10-100 nM; **=100 nM-1 μM; and *=>1 μM.

Cells were treated with the test compound at concentrations in the rangefrom 10 nM to 5 μM, and cell viability was determined after 96 hours bythe Trypan blue exclusion method. TABLE 7 Example # GI₅₀ for DU145,BT20, H157, DLD1 29 ** 30 * 31 *** 32 Not tested 33 ***

EXAMPLE 36 Radioprotective Effect of α,β-Unsaturated Sulfoxides onCultured Normal Human Cells

The radioprotective effect of α,β-unsaturated sulfoxides on culturednormal cells is evaluated as follows.

HFL-1 cells are plated into 24 well dishes at a cell density of 3000cells per 10 mm² in DMEM completed with 10% fetal bovine serum andantibiotics. α,β-Unsaturated sulfoxide test compound is added to thecells 24 hours later at concentrations 0.25, 0.5, 1.0 and 2.0micromolar, using DMSO as a solvent. Control cells are treated with DMSOalone. The cells are exposed to the test compound or DMSO for 24 hrs.The cells are then irradiated with either 10 Gy or 15 Gy of ionizingradiation (IR) using a J. L. Shepherd Mark 1, Model 30-1 Irradiatorequipped with ¹³⁷cesium as a source.

After irradiation, the medium on the test and control cells is removedand replaced with fresh growth medium without the test compounds orDMSO. The irradiated cells are incubated for 96 hours and duplicatewells are trypsinized and replated onto 100 mm² tissue culture dishes.The replated cells are grown under normal conditions with one change offresh medium for 3 weeks. The number of colonies from each 100 mm²culture dish, which represents the number of surviving cells, isdetermined by staining the dishes as described below.

To visualize and count the colonies derived from the clonal outgrowth ofindividual radioprotected cells, the medium is removed and the platesare washed one time with ambient temperature phosphate buffered saline.The cells are stained with a 1:10 diluted Modified Giemsa stainingsolution (Sigma) for 20 minutes. The stain is removed, and the platesare washed with tap water. The plates are air-dried, the number ofcolonies from each plate is counted and the average from duplicateplates is determined.

EXAMPLE 37 Effect of Exposure to Ionizing Radiation on Normal andMalignant Hematopoietic Progenitor Cell Growth After Pretreatment withα,β-Unsaturated Sulfoxides of the Invention

The effect of ionizing radiation on normal and malignant hematopoieticprogenitor cells which are pretreated with α,β-unsaturated sulfoxides ofthe invention is determined by assessing cloning efficiency anddevelopment of the pretreated cells after irradiation.

To obtain hematopoietic progenitor cells, human bone marrow cells (BMC)or peripheral blood cells (PB) are obtained from normal healthy, oracute or chronic myelogenous leukemia (AML, CML), volunteers byFicoll-Hypaque density gradient centrifugation, and are partiallyenriched for hematopoietic progenitor cells by positively selectingCD34⁺ cells with immunomagnetic beads (Dynal A. S., Oslo, Norway). TheCD34⁺ cells are suspended in supplemented alpha medium and incubatedwith mouse anti-HPCA-I antibody in 1:20 dilution, 45 minutes, at 4° C.with gentle inverting of tubes. Cells are washed ×3 in supplementedalpha medium, and then incubated with beads coated with the Fc fragmentof goat anti-mouse IgG, (75 μl of immunobeads/107 CD34⁺ cells). After 45minutes of incubation (4° C.), cells adherent to the beads arepositively selected using a magnetic particle concentrator as directedby the manufacturer.

2×10⁴ CD34⁺ cells are incubated in 5 mL polypropylene tubes (FisherScientific, Pittsburgh, Pa.) in a total volume of 0.4 mL of Iscove'smodified Dulbecco's medium (IMDM) containing 2% human AB serum and 10 mMHepes buffer. α,β-Unsaturated sulfoxide test compounds are added to thecells; in four different concentrations (0.25 μM, 0.5 μM, 1.0 μM and 2.0μM). Control cells receive DMSO alone. The cells are incubated for 20-24hours and irradiated with 5 Gy or 10 Gy of ionizing radiation.

Immediately after irradiation, the medium is removed and replaced withfresh medium without the test compound or DMSO. Twenty-four hours afterirradiation, the treatment and control cells are prepared for plating inplasma clot or methylcellulose cultures. Cells (1×10⁴ CD34⁺ cells perdish) are not washed before plating.

Assessment of the cloning efficiency and development of the treatedhematopoietic progenitor cells are carried out essentially as reportedin Gewirtz et al., Science 242, 1303-1306 (1988), the disclosure ofwhich is incorporated herein by reference.

EXAMPLE 38 Bone Marrow Purging with Ionizing Radiation AfterPretreatment with α,β-Unsaturated Sulfoxides of the Invention

Bone marrow is harvested from the iliac bones of an individual undergeneral anesthesia in an operating room using standard techniques.Multiple aspirations are taken into heparinized syringes. Sufficientmarrow is withdrawn so that the individual will be able to receive about4×10⁸ to about 8×10⁸ processed marrow cells per kg of body weight. Thus,about 750 to 1000 mL of marrow is withdrawn. The aspirated marrow istransferred immediately into a transport medium (TC-199, Gibco, GrandIsland, N.Y.) containing 10,000 units of preservative-free heparin per100 mL of medium. The aspirated marrow is filtered through threeprogressively finer meshes to obtain a cell suspension devoid ofcellular aggregates, debris and bone particles. The filtered marrow isthen processed further into an automated cell separator (e.g., Cobe 2991Cell Processor) which prepares a “buffy coat” product, (i.e., leukocytesdevoid of red cells and platelets). The buffy coat preparation is thenplaced in a transfer pack for further processing and storage. It may bestored until purging in liquid nitrogen using standard procedures.Alternatively, purging can be carried out immediately, then the purgedmarrow may be stored frozen in liquid nitrogen until it is ready fortransplantation.

The purging procedure is carried out as follows. Cells in the buffy coatpreparation are adjusted to a cell concentration of about 2×11⁷/mL inTC-199 containing about 20% autologous plasma. α,β-Unsaturatedsulfoxides of the invention, for example, at concentrations of from 0.25μM to 2.0 μM are added to the transfer packs containing the cellsuspension and incubated in a 37° C. waterbath for 20-24 hours withgentle shaking. The transfer packs are then exposed to 5-10 Gy ionizingradiation. Recombinant human hematopoietic growth factors, e.g., rH IL-3or rH GM-CSF, may be added to the suspension to stimulate growth ofhematopoietic neoplasms and thereby increase their sensitivity toionizing radiation.

The cells may then either be frozen in liquid nitrogen or washed once at4° C. in TC-199 containing about 20% autologous plasma. Washed cells arethen infused into the individual. Care must be taken to work understerile conditions wherever possible and to maintain scrupulous aseptictechniques at all times.

All references cited herein are incorporated by reference. The presentinvention may be embodied in other specific forms without departing fromthe spirit or essential attributes thereof and, accordingly, referenceshould be made to the appended claims, rather than to the foregoingspecification, as indication the scope of the invention.

1. A compound according to Formula I:

wherein, A is substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; B is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, provided that when A and B areboth phenyl, at least one of A or B is substituted; n is 0 or 1; R¹ is—H, —(C₁-C₈)hydrocarbyl, —CN, —CO₂(C₁-C₆)alkyl or halo(C₁-C₆)alkyl; theconformation of the substituents on the carbon-carbon double bond iseither E- or Z-; the conformation of the substituents on the sulfoxidesulfur atom is R—, S— or any mixture of R— and S—; * indicates that,when R¹ is other than —H, the conformation of the substituents on thedesignated carbon atom is R—, S— or any mixture of R— and S—; or a saltof such a compound.
 2. A compound according to claim 1 of Formula Iz:


3. A compound according to claim 1 of the Formula Ie:


4. A compound according to claim 1 of Formula IA:

wherein: A¹ and B¹ are independently aryl or heteroaryl; x and y areindependently 0, 1, 2, 3, 4 or 5, provided that the highest value of xor y is equal to the number of substitutable hydrogen atoms in the ringto which x or y is attached, and when A¹ and B¹ are both phenyl, the sumof x and y is greater than zero; each R^(a) is independently selectedfrom the group consisting of halogen; —(C₁-C₈)hydrocarbyl, —C(═O)R²,—NR² ₂, —NHC(═O)R³, —NHSO₂R³, —NHR⁴, —NHCR²R⁴C(═O)R⁶, —C(═O)OR²,—C(═O)NHR²; —NO₂, —CN, —OR², —P(═O)(OH)₂, dimethylamino(C₂-C₆ alkoxy),—NHC(═NH)NHR², —(C₁-C₆)haloalkyl, —(C₁-C₆)haloalkoxy and —N═CH—R⁷; eachR^(b) is independently selected from the group consisting of—(C₁-C₈)hydrocarbyl, —C(═O)R², halogen, —NO₂, —CN, —OR², —C(═O)OR², —NR²₂, (C₁-C₆)haloalkyl and (C₁-C₆)haloalkoxy; each R² is independentlyselected from the group consisting of —H and —(C₁-C₈)hydrocarbyl; eachR³ is independently selected from the group consisting of —H,—(C₁-C₈)hydrocarbyl, —O(C₁-C₈)hydrocarbyl, substituted and unsubstitutedaryl, substituted heterocyclyl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl,—(C₂-C₁₀)heteroalkyl, —(C₁-C₆)haloalkyl, —CR²R⁴NHR⁵, —N(R²)₂,—(C₁-C₃)alkyleneNH₂, —(C₁-C₃)alkylene-N(CH₃)₂,—(C₁-C₃)perfluoroalkylene-N(CH₃)₂, —(C₁-C₃)alkylene-N⁺(C₁-C₃)₃,—(C₁-C₃)alkylene-N⁺(CH₂CH₂OH)₃, —(C₁-C₃)alkylene-OR²,—(C₁-C₄)alkylene-CO₂R², —(C₁-C₄)alkylene-C(═O)halogen,halo(C₁-C₃)alkyl-, —(C₁-C₃)alkylene-C(═O)(C₁-C₃)alkyl, and—(C₁-C₄)perfluoroalkylene-CO₂R²; each R⁴ is independently selected fromthe group consisting of —H, —(C₁-C₆)alkyl, —(CH₂)₃—NH—C(NH₂)(═NH),—CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH, —(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH,—CH₂-(2-imidazolyl), —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl,—CH₂—OH, —CH(OH)—CH₃, —CH₂-(3-indolyl), and —CH₂-(4-hydroxyphenyl); eachR⁵ is independently selected from the group consisting of —H and acarboxy terminally linked peptidyl residue containing from 1 to 3 aminoacids in which the terminal amino group of the peptidyl residue ispresent as a functional group selected from the group consisting of —NH₂and —NHC(═O)(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N(C₁-C₆ alkyl)₂ and—NHC(═O)O(C₁-C₇)hydrocarbyl; each R⁶ is independently selected from thegroup consisting of —OR² and an N-terminally linked peptidyl residuecontaining from 1 to 3 amino acids in which the terminal carboxyl groupof the peptidyl residue is present as a functional group selected fromthe group consisting of —CO₂R² and —C(═O)NR² ₂; and each R⁷ isindependently selected from the group consisting of substituted andunsubstituted aryl and substituted and unsubstituted heteroaryl.
 5. Acompound according to claim 4 wherein the sum of x and y is greater thanzero.
 6. A compound according to claim 5 wherein Al is an aryl radical.7. A compound according to claim 6 selected from the group consistingof: (1E)-2-(4-fluorophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-4-chlorophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(4-bromophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(2-nitrophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(3-nitrophenyl)-1-[(naphthylmethyl)sulfinyl]ethene;(1E)-2-(4-nitrophenyl)-1-[(naphthylmethyl)sulfinyl]ethene; and saltsthereof.
 8. A compound according to claim 6, of Formula IB:


9. A compound according to claim 8, wherein each R^(a) is independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —NO₂, —CN, —C(═O)OR², —OH, —NH₂, (C₁-C₆)trifluoroalkoxyand —CF₃.
 10. A compound according to claim 9, of Formula IC:


11. A compound according to claim 10 wherein each R^(a) and each R^(b)are independently selected from the group consisting of halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —NO₂, —CN and —CF₃.
 12. A compoundaccording to claim 10 wherein the conformation of the substituents onthe carbon-carbon double bond is E-.
 13. A compound according to claim12 wherein x and y are independently 0, 1 or
 2. 14. A compound accordingto claim 12 selected from the group consisting of:(1E)-1-{[(3-amino-4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethane;(1E)-1-{[(3-hydroxy-4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethane;(1E)-1-{[(4-methoxy-3-nitrophenyl)methyl]-sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethane;2-({[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]amino}sulfonyl)aceticacid;2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}aceticacid;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]aminocarboxamidine;2-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]amino}aceticacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](3,5-dinitrophenyl)carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](3,5-diaminophenyl)carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-chloroacetamide;N-[5-({[(1E)-2-2,4,6-trimethoxyphenyl)vinyl]sulfinyl)methyl)-2-methoxyphenyl]-2-(4-methylpiperazinyl)acetamide;N-[5-({[1(E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-benzamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](4-nitrophenyl)carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](4-aminophenyl)carboxamide;(1E)-1-[({3-[(1Z)-1-aza-2-(4-nitrophenyl)vinyl]-4-methoxyphenyl}methyl)-sulfinyl]-2-(2,4,6-trimethoxyphenyl)ethene;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](2R)-2,6-diaminohexanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](2R)-2-amino-3-hydroxypropanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl](2S)-2-amino-3-hydroxypropanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]aminoamide;(1E)-1-({[4-methoxy-3-(methylamino)phenyl]-methyl}sulfinyl)-2-(2,4,6-trimethoxyphenyl)ethene;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]acetamide;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-[(2,4dinitrophenyl)sulfonyl]amine;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl][(2,4-diaminophenyl)sulfonyl]amine;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(dimethylamino)acetamide;2-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]amino}propanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl][4-(4-methylpiperazinyl)phenyl]carboxamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-hydroxyacetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-pyridylacetamide;{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]carbamoyl}methylacetate;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-hydroxypropanamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(triethylamino)acetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]-2-[tris(2-hydroxyethyl)amino]acetamide;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-hydroxy-2-methylpropanamide;1-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-isopropylacetate;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2,2,2-trifluoroacetamide;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl][(trifluoromethyl)sulfonyl]amine;3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]carbamoyl}-propanoicacid;3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}propanoylchloride;3-[({N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-methyl)oxycarbonyl]propanoicacid;4-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}butanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(phosphonooxy)acetamide,disodium salt;4-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]amino}butanoicacid;3-{[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-amino}propanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]methoxycarboxamide;[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl][(4-methoxyphenyl)sulfonyl]amine;{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}ethylacetate;methyl-3-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}-propanoate;ethyl-2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]carbamoyl}acetate;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2,2,3,3,3-pentafluoropropanamide;methyl-2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]-sulfinyl}methyl)-2-methoxyphenyl]carbamoyl}-2,2-difluoroacetate;3-{N-[5-({[(1E)-2-2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]-carbamoyl}-2,2,3,3-tetrafluoropropanoicacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-aminoacetamide;2-{N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}-methyl)-2-methoxyphenyl]-carbamoyl}-2,2-difluoroaceticacid;N-[5-({[(1E)-2-(2,4,6-trimethoxyphenyl)vinyl]sulfinyl}methyl)-2-methoxyphenyl]-2-(dimethylamino)-2,2-difluoroacetamide,4-((1E)-2-{[(4-fluorophenyl)methyl]sulfinyl}vinyl)benzoic acid;4-((1E)-2-{[(4-iodophenyl)methyl]sulfinyl}vinyl)benzoic acid;4-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)benzoic acid;1-[5-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)-2-fluoro-phenyl]-2-(dimethylamino)ethan-1-one;(1E)-2-(2,4-difluorophenyl)-1-{[(4-bromophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-amino-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-2-(4-fluorophenyl)-1-{[(2,3,4,5,6-pentafluorophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-chlorophenyl)-1-{[(2,3,4,5,6-pentafluorophenyl)-methyl]sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(2,3,4,5,6-pentafluorophenyl)-methyl]sulfinyl}ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]-sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(2,3,4,5,6-pentafluorophenyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(2-hydroxy-3,5-dinitrophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-methyl-2,4-dimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3,4,5-trimethoxyphenyl)ethene;(1E)-1-{[(2-nitro-4,5-dimethoxyphenyl)methyl]-sulfinyl}2-(3,4,5-trimethoxyphenyl)ethene;(1E)-1-{[(2-nitro-4,5-dimethoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(2-nitro-4,5-dimethoxyphenyl)methyl]sulfinyl}-2-(3-methyl-2,4-dimethoxyphenyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2,3,4-trifluorophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,3,4-trifluorophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,6-methoxy-4-hydroxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,3,5,6-tetrafluorophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,5-trimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,3,4-trimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-nitro-4-hydroxy-5-methoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3,4-dimethoxy-6-nitrophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3,4-dimethoxy-5-iodophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,6-dimethoxy-4-fluorophenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2-hydroxy-4,6-dimethoxyphenyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethylphenyl)ethene;(1E)-1-{[(4chlorophenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2,6-dimethoxy-4-fluorophenyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-hydroxy-4,6-dimethoxyphenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2,6-dimethoxy-4-fluorophenyl)ethene;(1E)-1-{[(2,4,6-trimethoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(2,3,4-trimethoxyphenyl)methyl]sulfinyl}-2-(2,6-dimethoxyphenyl)ethene;(1E)-1-{[(3,4,5-trimethoxyphenyl)methyl]sulfinyl}-2-(2,4,6-trimethoxyphenyl)ethene;(1E)-1-{[(3,4,5-trimethoxyphenyl)methyl]sulfinyl}-2-(2,6-dimethoxyphenyl)ethene;(1E)-1-{[(3,4,5-trimethoxyphenyl)methyl]sulfinyl}-2-(4-fluorophenyl)ethene;(1E)-2-(4-fluorophenyl)-1-({[4-(trifluoromethyl)phenyl]methyl}-sulfinyl)ethene;(1E)-2-(4-chlorophenyl)-1-({[4-(trifluoromethyl)phenyl]methyl}-sulfinyl)ethene;(1E)-2-(4-bromophenyl)-1-({[4-(trifluoromethyl)phenyl]methyl}-sulfinyl)ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(4-fluorophenyl)ethene;(1E)-1-{[(2,4dichlorophenyl)methyl]sulfinyl}-2-(4-chloro-phenyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(4-fluoro-phenyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(4-chloro-phenyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(4-bromo-phenyl)ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-nitrophenyl)methyl]sulfinyl}-ethene;4-({[(1E)-2-(4-fluorophenyl)vinyl]sulfinyl}methyl)benzene-carbonitrile;4-({[(1E)-2-(4-chlorophenyl)vinyl]sulfinyl}methyl)benzene-carbonitrile;4-({[(1E)-2-(4-bromophenyl)vinyl]sulfinyl}methyl)benzene-carbonitrile;(1E)-2-(3,4-difluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-chloro-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-chloro-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2,3-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-iodophenyl)methyl]-sulfinyl}ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(4-iodophenyl)-ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(4-iodophenyl)-ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-iodophenyl)-ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-chlorophenyl)-ethene;(1E)-2-(4-bromophenyl)-1-{[(4-iodophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(4-nitrophenyl)-ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(2-nitrophenyl)-ethene;(1E)-2-(4-iodophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]-sulfinyl}-2-(4-iodophenyl)-ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3,4-dichlorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(3-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}-ethene;(1E)-2-(4-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}-ethene;(1E)-2-(2-trifluoromethyl-4-fluorophenyl)-1-{[(4-fluorophenyl)-methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(2-trifluoromethylphenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(3-trifluoromethylphenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-trifluoromethylphenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-trifluoromethyl-4-fluorophenyl)-1-{[(4-chlorophenyl)-methyl]sulfinyl}ethene;(1E)-2-(3-methyl-4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(2-trifluoromethyl-4-fluorophenyl)-1-{[(2,4-dichloro-phenyl)methyl]sulfinyl}-ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-trifluoromethylphenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(3-trifluoromethylphenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-2-4-trifluoromethylphenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-cyanophenyl)methyl]sulfinyl}ethene;(1E)-2-3-nitrophenyl)-1-{[(4-cyanophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-cyanophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(4-methylphenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}-ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-methylphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-chlorophenyl)-1-{[(4-methoxyphenyl)methyl]-sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(4-methoxyphenyl)methyl]-sulfinyl}ethene;(1E)-2-(2-nitrophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(3-nitrophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-nitrophenyl)-1-{[(4-methoxyphenyl)methyl]sulfinyl}ethene;(1E)-2-(4-chlorophenyl)-1-{[(4-nitrophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-nitrophenyl)methyl]-sulfinyl}ethene; andsalts thereof.
 15. A compound according to claim 10 wherein: R^(a) isselected from the group consisting of chlorine, fluorine and bromine,and said R^(a) is bonded to the para position of the ring to which it isattached; x is 0 or 1; R^(b) is selected from the group consisting ofchlorine, fluorine, bromine, methyl and methoxy, and said R^(b) isbonded to the ortho or para position of the ring to which it is bonded;and y is 0, 1, 2 or
 3. 16. A compound according to claim 15 wherein theconformation of the substituents on the carbon-carbon double bond is E-.17. A compound according to claim 16 selected from the group consistingof: (1E)-2-(2-chlorophenyl)-1-[benzylsulfinyl]ethene;(1E)-2-(4-chlorophenyl)-1-[benzylsulfinyl]ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(4-fluorophenyl)ethene;(1E)-2-(4-chlorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1E)-2-(4-fluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-2-(2,4-difluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-fluorophenyl)ethene;(1E)-2-(4-bromophenyl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene;(1E)-2-(4-bromophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-1-{[(4-bromophenyl)methyl]-sulfinyl}-2-(4-chlorophenyl)ethene; andsalts thereof.
 18. A compound according to claim 10, wherein: each ofR^(a) and R^(b) are independently selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halogen and nitro, and are bonded to theortho or para position of the ring to which they are attached; and x andy are independently 0, 1, 2 or
 3. 19. A compound according to claim 18wherein the conformation of the substituents on the carbon-carbon doublebond is Z-.
 20. A compound according to claim 19 selected from the groupconsisting of: (1Z)-2-phenyl-1-[benzylsulfinyl]ethene;(1Z)-1-{[(4-chlorophenyl)methyl]-sulfinyl}-2-phenylethene;(1Z)-1-{[(2-chlorophenyl)methyl]sulfinyl}-2-phenylethene;(1Z)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-phenylethene;(1Z)-2-(4-chlorophenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-chlorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1Z)-2-(4-chlorophenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}-ethene;(1Z)-2-(4-chlorophenyl)-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-fluorophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-bromophenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-bromophenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}-ethene;(1Z)-2-(4-bromophenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-bromophenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-methylphenyl)-1-[benzylsulfinyl]ethene;(1Z)-2-(4-methylphenyl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-methylphenyl)-1-{[(2-chlorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-methylphenyl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1Z)-2-(4-fluorophenyl)-1-{[(4-iodophenyl)methyl]sulfinyl}-ethene; andsalts thereof.
 21. A compound according to claim 5, of Formula ID:

wherein B² is selected from the group consisting of heteroaryl and arylother than phenyl.
 22. A compound according to claim 21 wherein B² isheteroaryl.
 23. A compound according to claim 21 wherein B² is selectedfrom the group consisting of furyl, thienyl, pyrrolyl, thiazolyl,pyridyl, thienyl-1-dioxide, anthryl, and naphthyl.
 24. A compoundaccording to claim 23 wherein the conformation of the substituents onthe carbon-carbon double bond is E-.
 25. A compound according to claim24 wherein R^(a) is independently selected from the group consisting ofhalogen, (C₁-C₃)alkoxy, —CN, —NO₂, and —CF₃.
 26. A compound of claim 25selected from the group consisting of:(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-pyridyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(3-pyridyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(4-pyridyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-pyridyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(3-pyridyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(4-pyridyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-pyridyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(3-pyridyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(4-pyridyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-thienyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-thienyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-thienyl)ethene;(1E)-2-(4-bromo(2-thienyl))-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(5-bromo(2-thienyl))-1-{[(4-fluorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(5-bromo(2-thienyl))-1-{[(4-chlorophenyl)methyl]-sulfinyl}ethene;(1E)-2-(5-bromo(2-thienyl))-1-{[(4-bromophenyl)methyl]-sulfinyl}ethene;2-((1E)-2-{[4-fluorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;2-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;2-((1E)-2-{[(4-bromophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-methylphenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-trifluoromethylphenyl)methyl]sulfinyl}-2-(3-thienyl)-ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(3-thienyl)-ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(3-thienyl)-ethene;(1E)-1-{[(4-cyanophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;(1E)-1-{[(4-nitrophenyl)methyl]sulfinyl}-2-(3-thienyl)ethene;3-((1E)-2-{[(4-fluorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(4-chlorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(4-bromophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(4-methoxyphenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;3-((1E)-2-{[(2,4-dichlorophenyl)methyl]sulfinyl}vinyl)thiole-1,1-dione;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-furyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-furyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-furyl)ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-3-furyl)ethene;(1E)-1-{[(4-methylphenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-trifluoromethylphenyl)methyl]sulfinyl}-2-(3-furyl)-ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(3,4-dichlorophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-cyanophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-nitrophenyl)methyl]sulfinyl}-2-(3-furyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(1,3-thiazol-2-yl)-ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-pyrrol-2-ylethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-pyrrol-2-ylethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(4-iodophenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(2,4-dichlorophenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(4-methoxyphenyl)methyl]sulfinyl}-2-(5-nitro(3-thienyl))ethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-naphthylethene;(1E)-1-{[(4-fluorophenyl)methyl]sulfinyl}-2-(2-naphthyl)ethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-naphthylethene;(1E)-1-{[(4-chlorophenyl)methyl]sulfinyl}-2-(2-naphthyl)ethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-naphthylethene;(1E)-1-{[(4-bromophenyl)methyl]sulfinyl}-2-(2-naphthyl)ethene;(1E)-2-(9-anthryl)-1-{[(4-fluorophenyl)methyl]sulfinyl}ethene;(1E)-2-(9-anthryl)-1-{[(4-chlorophenyl)methyl]sulfinyl}ethene;(1E)-2-(9-anthryl)-1-{[(4-bromophenyl)methyl]sulfinyl}ethene; and saltsthereof.
 27. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound according to claim
 1. 28. A conjugateof the Formula, I-L-Ab; wherein: I is a compound according to claim 1;Ab is an antibody; and -L- is a single covalent bond or a linking groupcovalently linking said compound to said antibody.
 29. A conjugateaccording to claim 28 wherein said antibody Ab is a monoclonal antibodyor a monospecific polyclonal antibody.
 30. A conjugate according toclaim 29 wherein said antibody Ab is a tumor-specific antibody.
 31. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and at least one conjugate according to claim
 28. 32. A methodof treating an individual for a proliferative disorder comprisingadministering to said individual an effective amount of a compoundaccording to claim
 1. 33. A method according to claim 32 wherein theproliferative disorder is selected from the group consisting ofhemangiomatosis in newborn; secondary progressive multiple sclerosis;chronic progressive myelodegenerative disease; neurofibromatosis;ganglioneuromatosis; keloid formation; Paget's Disease of the bone;fibrocystic disease, sarcoidosis; Peronies and Duputren's fibrosis,cirrhosis, atherosclerosis and vascular restenosis.
 34. A methodaccording to claim 32 wherein the proliferative disorder is cancer. 35.A method according to claim 34 wherein the cancer is selected from thegroup consisting of ovarian, breast, prostate, testicular, lung, renal,colorectal skin, and brain cancers, or the cancer is a leukemia.
 36. Themethod of claim 35, further comprising administering an effective amountof therapeutic ionizing radiation to the individual.
 37. A method ofinducing apoptosis of tumor cells in an individual afflicted with cancercomprising administering to said individual an effective amount of acompound according to claim
 1. 38. A method according to claim 37wherein the tumor cells are selected from the group consisting ofovarian, breast, prostate, lung, colorectal, renal and brain tumors. 39.A method of treating an individual afflicted with cancer, comprisingadministering to said individual an effective amount of at least oneconjugate according to claim
 28. 40. A method of reducing or eliminatingthe effects of ionizing radiation on normal cells in an individual whohas incurred or is at risk of incurring exposure to ionizing radiation,comprising administering an effective amount of at least oneradioprotective compound according to claim 1 to the individual prior toor after exposure to ionizing radiation.
 41. The method of claim 40wherein the radioprotective compound is administered before theindividual is exposed to the ionizing radiation.
 42. The method of claim41, wherein the radioprotective compound is administered at least aboutfour hours before the individual is exposed to the ionizing radiation.43. The method of claim 42, wherein the radioprotective compound isadministered no more than about twenty-four hours before the individualis exposed to the ionizing radiation.
 44. The method of claim 43,wherein the radioprotective compound is administered about eighteen andabout six hours before the individual is exposed to the ionizingradiation.
 45. The method of claim 40, wherein the radioprotectivecompound is administered after the individual is exposed to the ionizingradiation.
 46. The method of claim 45, wherein the radioprotectivecompound is administered between zero and six hours after the individualis exposed to the ionizing radiation.
 47. A method of treating anindividual for a proliferative disorder, comprising: (a) administeringto the individual an effective amount of at least one radioprotectivecompound according to claim 1; and (b) administering an effective amountof therapeutic ionizing radiation.
 48. The method of claim 47, whereinthe proliferative disorder is cancer.
 49. A method of reducing thenumber of malignant cells in bone marrow of an individual, comprising:(a) removing a portion of the individual's bone marrow; (b)administering an effective amount of at least one radioprotectivecompound according to claim 1 to the bone marrow; (c) irradiating thebone marrow with an effective amount of ionizing radiation.
 50. Themethod of claim 49, further comprising reimplanting the bone marrow intothe individual.
 51. The method of claim 49, wherein the individualreceives therapeutic ionizing radiation prior to reimplantation of thebone marrow, and is administered at least one radioprotective compoundof claim 1 prior to receiving the therapeutic ionizing radiation. 52.The method of claim 49 wherein the radioprotective compound isadministered at least about 6 hours before exposure of the bone marrowto the ionizing radiation.
 53. The method of to claim 49 wherein theradioprotective compound is administered about 20 hours before exposureto the ionizing radiation.
 54. The method of claim 49 wherein theradioprotective compound is administered about 24 hours before exposureto the ionizing radiation.
 55. A method for protecting an individualfrom cytotoxic side effects of the administration of a mitotic phasecell cycle inhibitor or a topoisomerase inhibitor comprisingadministering to the individual, in advance of administration of saidinhibitor, an effective amount of at least one cytoprotective compoundaccording to claim 1, wherein the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor is not a compound according to claim
 1. 56. Themethod according to claim 55 wherein the mitotic phase cell cycleinhibitor is selected from the group consisting of vinca alkaloids,taxanes, naturally occurring macrolides, and colchicine and itsderivatives.
 57. The method according to claim 56 wherein the mitoticphase cell cycle inhibitor is selected from the group consisting ofpaclitaxel and vincristine.
 58. The method according to claim 55 whereinthe topoisomerase inhibitor is selected from the group consisting ofcamptothecin, etoposide and mitoxantrone.
 59. The method according toclaim 55 wherein the cytoprotective compound is administered at leastabout 1 hours before administration of the mitotic phase cell cycleinhibitor or topoisomerase inhibitor.
 60. The method according to claim59 wherein the cytoprotective compound is administered at least about 12hours before administration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 61. The method according to claim 60 whereinthe cytoprotective compound is administered at least about 24 hoursbefore administration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 62. A method for treating cancer or otherproliferative disorder comprising administering to an individual aneffective amount at least one cytoprotective compound according to claim1 followed by an effective amount of at least one mitotic phase cellcycle inhibitor or topoisomerase inhibitor after administration of thecytoprotective compound according to claim
 1. 63. The method accordingto claim 62 wherein the mitotic phase cell cycle inhibitor is selectedfrom the group consisting of vinca alkaloids, taxanes, naturallyoccurring macrolides, and colchicine and its derivatives.
 64. The methodaccording to claim 63 wherein the mitotic phase cell cycle inhibitor isselected from the group consisting of paclitaxel and vincristine. 65.The method according to claim 62 wherein the topoisomerase inhibitor isselected from the group consisting of camptothecin, etoposide andmitoxantrone.
 66. The method according to claim 62 wherein thecytoprotective compound is administered at least about 1 hour beforeadministration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 67. The method according to claim 66 whereinthe cytoprotective compound is administered at least about 12 hoursbefore administration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 68. The method according to claim 67 whereinthe cytoprotective compound is administered at least about 24 hoursbefore administration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 69. A process for preparing a compoundaccording to claim 3 comprising: (a) reacting a compound of Formula II:

wherein A is substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; n is 0 or 1; and R¹ is —H,—(C₁-C₈)hydrocarbyl, —CN, —CO₂(C₁-C₆)alkyl or halo(C₁-C₆)alkyl; with acompound of Formula III:

wherein B is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; and (b) isolating a compound according toclaim 3 from the reaction products.
 70. A process according to claim 69wherein the compound of Formula II is prepared by; (a) reacting acompound of Formula IIA:

with an oxidizing agent capable of oxidizing a sulfide to a sulfoxide;and (b) isolating a compound of Formula II from the reaction products.71. A process according to claim 70 wherein the compound of Formula IIAis prepared by: (a) reacting a compound of Formula IIB:

wherein: L is a leaving group; with mercaptoacetic acid; and (b)isolating a compound of Formula IIA from the reaction products.
 72. Aprocess for preparing a compound according to claim 2 comprising: (a)reacting a compound of Formula IV:

wherein: A is substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; B is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; n is 0 or 1; and R¹ is —H,—(C₁-C₈)hydrocarbyl, —CN, —CO₂(C₁-C₆)alkyl or halo(C₁-C₆)alkyl; with anoxidizing agent capable of oxidizing a sulfide to a sulfoxide; and (b)isolating a compound according to claim 2 from the reaction products.73. A process according to claim 72 wherein the compound of Formula IVis prepared by: (a) reacting a compound of Formula IVA:

wherein Q⁺ is a counterion selected from the group consisting of alkalimetals, alkaline earth metals and transition metals; with a compound ofFormula IVB:

(b) isolating a compound of Formula IV from the reaction products.
 74. Aprocess for preparing a compound according to Formula V:

wherein: A is substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; B is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, provided that when A and B areboth phenyl, at least one of A or B is substituted; n is 0 or 1; R¹ is—H, —(C₁-C₈)hydrocarbyl, —CN, —CO₂(C₁-C₆)alkyl or halo(C₁-C₆)alkyl; theconformation of the substituents on the carbon-carbon double bond iseither E- or Z-; and * indicates that, when R¹ is other than —H, theconformation of the substituents on the designated carbon atom is R—, S—or any mixture of R— and S—; or a salt of such a compound; comprisingthe steps of: (a) reacting a compound according to Formula I:

wherein A, B, n, R¹ and * are so defined; A is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; theconformation of the substituents on the carbon-carbon double bond iseither E- or Z-; and the conformation of the substituents on thesulfoxide sulfur atom is R—, S— or any mixture of R— and S—; or a saltthereof; with an oxidizing agent capable of oxidizing a sulfoxide to asulfone; and (b) isolating a compound according to Formula V from thereaction products.
 75. A compound according to Formula II:

wherein: A is substituted or unsubstituted aryl other than unsubstitutedphenyl, or substituted or unsubstituted heteroaryl; n is 0 or 1; and R¹is —H, —(C₁-C₈)hydrocarbyl, —CN, —CO₂(C₁-C₆)alkyl or halo(C₁-C₆)alkyl;the conformation of the substituents on the sulfoxide sulfur atom is R—,S— or any mixture of R— and S—; and * indicates that, when R¹ is otherthan —H, the conformation of the substituents on the designated carbonatom is R—, S— or any mixture of R— and S—; or a salt of such acompound.
 76. A compound according to Formula IV:

wherein: A and B are substituted or unsubstituted aryl other thanunsubstituted phenyl, or substituted or unsubstituted heteroaryl; n is 0or 1; and R¹ is —H, —(C₁-C₈)hydrocarbyl, —CN, —CO₂(C₁-C₆)alkyl orhalo(C₁-C₆)alkyl; the conformation of the substituents on the sulfoxidesulfur atom is R—, S— or any mixture of R— and S—; and * indicates that,when R¹ is other than —H, the conformation of the substituents on thedesignated carbon atom is R—, S— or any mixture of R— and S—; or a saltof such a compound.
 77. An isolated optical isomer of a compoundaccording to claim 1.